Solid forms of selective androgen receptor modulators

ABSTRACT

The present invention relates to solid forms of (S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2-methylpropanamide and process for producing the same.

CROSS REFERENCE TO RELATED APPLICATIONS

This Application is a divisional application of U.S. application Ser.No. 12/228,100, filed on Sep. 29, 2008, now U.S. Pat. No.7,968,603,which is a continuation in part of U.S. application Ser. No.12/209,137, filed on Sep. 11, 2008, now U.S. Pat. No. 7,977,386, whichclaims the benefit of U.S. Provisional Application Ser. No. 60/960,012,filed on Sep. 11, 2007, which are incorporated in their entirety hereinby reference.

FIELD OF INVENTION

The present invention relates to solid forms of (R) or(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2-methylpropanamideand processes of preparation thereof.

BACKGROUND OF THE INVENTION

The androgen receptor (“AR”) is a ligand-activated transcriptionalregulatory protein that mediates induction of male sexual developmentand function through its activity with endogenous androgens. Androgensare generally known as the male sex hormones. The androgenic hormonesare steroids which are produced in the body by the testes and the cortexof the adrenal gland or can be synthesized in the laboratory. Androgenicsteroids play an important role in many physiologic processes, includingthe development and maintenance of male sexual characteristics such asmuscle and bone mass, prostate growth, spermatogenesis, and the malehair pattern (Matsumoto, Endocrinol. Met. Clin. N. Am. 23:857-75(1994)). The endogenous steroidal androgens include testosterone anddihydrotestosterone (“DHT”). Testosterone is the principal steroidsecreted by the testes and is the primary circulating androgen found inthe plasma of males. Testosterone is converted to DHT by the enzyme 5alpha-reductase in many peripheral tissues. DHT is thus thought to serveas the intracellular mediator for most androgen actions (Zhou, et al.,Molec. Endocrinol. 9:208-18 (1995)). Other steroidal androgens includeesters of testosterone, such as the cypionate, propionate,phenylpropionate, cyclopentylpropionate, isocarporate, enanthate, anddecanoate esters, and other synthetic androgens such as7-Methyl-Nortestosterone (“MENT’) and its acetate ester (Sundaram etal., “7 Alpha-Methyl-Nortestosterone (MENT): The Optimal Androgen ForMale Contraception,” Ann. Med., 25:199-205 (1993) (“Sundaram”). Becausethe AR is involved in male sexual development and function, the AR is alikely target for effecting male contraception or other forms of hormonereplacement therapy.

New innovative approaches are urgently needed at both the basic scienceand clinical levels to develop compounds which are useful for a) malecontraception; b) treatment of a variety of hormone-related conditions,for example conditions associated with Androgen Decline in Aging Male(ADAM), such as fatigue, depression, decreased libido, sexualdysfunction, erectile dysfunction, hypogonadism, osteoporosis, hairloss, anemia, obesity, sarcopenia, osteopenia, osteoporosis, benignprostate hyperplasia, alterations in mood and cognition and prostatecancer; c) treatment of conditions associated with ADIF, such as sexualdysfunction, decreased sexual libido, hypogonadism, sarcopenia,osteopenia, osteoporosis, alterations in cognition and mood, depression,anemia, hair loss, obesity, endometriosis, breast cancer, uterine cancerand ovarian cancer; d) treatment and/or prevention of acute and/orchronic muscular wasting conditions; e) preventing and/or treating dryeye conditions; f) oral androgen replacement therapy; and/or g)decreasing the incidence of, halting or causing a regression of prostatecancer.

Polymorphs, solvates and salts of various drugs have been described inthe literature as imparting novel properties to the drugs. Organic smalldrug molecules have a tendency to self-assemble into various polymorphicforms depending on the environment that drives the self assembly. Heatand solvent mediated effects can also lead to changes that transform onepolymorphic form into another.

Identifying which polymorphic form is the most stable under eachcondition of interest and the processes that lead to changes in thepolymorphic form is crucial to the design of the drug manufacturingprocess in order to ensure that the final product is in its preferredpolymorphic form. Different polymorphic forms of an activepharmaceutical ingredient (API) can lead to changes in the drug'ssolubility, dissolution rate, pharmacokinetics and ultimately itsbioavailability and efficacy in patients.

SUMMARY OF THE INVENTION

In one embodiment, the present invention relates to solid forms of (R)or(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2-methylpropanamideand processes of preparation thereof. In some embodiments such compoundsare useful for their androgenic and anabolic activity. (R) or(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2-methylpropanamideare selective androgen receptor modulators (SARMs) useful for a) malecontraception; b) treatment of a variety of hormone-related conditions,for example conditions associated with Androgen Decline in Aging Male(ADAM); c) treatment of conditions associated with Androgen Decline inFemale (ADIF); d) treatment and/or prevention of chronic muscularwasting; and/or; e) decreasing the incidence of, halting or causing aregression of prostate cancer; f) oral androgen replacement and/or otherclinical therapeutic and/or diagnostic areas.

In one embodiment the present invention provides, a crystalline form of(R) or(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2-methylpropanamidecompound.

In one embodiment the present invention provides, an anhydrouscrystalline form of (R) or(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2-methylpropanamidecompound.

In another embodiment this invention provides, a composition comprisinga therapeutic amount of crystalline form of an anhydrous crystallineform of (R) or(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2-methylpropanamideand a suitable carrier or diluent.

In one embodiment this invention provides, a process for the preparationof a crystalline form of (R) or(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2-methylpropanamidesaid process comprising dissolving (R) or(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2-methylpropanamidein at least one organic solvent at a temperature of between about −20°C. to +5° C. under conditions permissive to crystallization, therebyobtaining said crystalline form.

In one embodiment, this invention provides, a paracrystalline (R) or(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2-methylpropanamidecompound.

In another embodiment, this invention provides, a composition comprisingparacrystalline form of (R) or(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2-methylpropanamideand a suitable carrier or diluent.

In one embodiment, this invention provides, a process for thepreparation of paracrystalline (R) or(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2-methylpropanamidecomprising stirring a suspension of a crystalline form of (R) or(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2-methylpropanamidein water at ambient temperature of about 20-30° C. for at least 0.5hours, to obtain a paracrystalline compound.

In one embodiment this invention provides, a composition comprising amixture of crystalline and paracrystalline solid forms of (R) or(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2-methylpropanamidecompound and a suitable carrier or diluent.

BRIEF DESCRIPTION OF THE DRAWINGS

The subject matter regarded as the invention is particularly pointed outand distinctly claimed in the concluding portion of the specification.The invention, however, both as to organization and method of operation,together with objects, features, and advantages thereof, may best beunderstood by reference to the following detailed description when readwith the accompanying drawings in which:

FIG. 1 schematically depicts the synthesis of racemic mixtures ofcompound 1.

FIG. 2 schematically depicts the synthesis of the (S)-enantiomer ofcompound S-1.

FIG. 3 schematically depicts the synthesis of the (R)-enantiomer ofcompound R-1.

FIG. 4A-4D depict XRPD patterns for solid forms of Compound S-1.4A—solid form A-batch P1 of compound S-1; 4B—solid form A-batch P2 ofcompound S-1; 4C—solid form A-batch P3 of compound S-1; 4D—solid formB′-batch P4 of compound S-1.

FIG. 5A-5D are Raman spectra of sample batches P1-P4 of compound S-1,respectively. The laser power setting was 100 mW, at a resolution of 2cm⁻¹.

FIG. 6A-6D are TG-FTIR spectra of sample batches P1-P4 of compound S-1,respectively. Conditions included a temperature range operation in thedynamic mode of 25° C./10.0/250° C., in an N₂ atmosphere.

FIG. 7A-7D are DSC spectra of sample batches P1-P4 of compound S-1,respectively. The asterisk indicates a settling effect, an artifact ofthe machinery used.

FIGS. 8A, 8B and 8C, are SEM micrographs of sample batches P1, P2 and P4of compound S-1, respectively.

FIGS. 9A, 9B and 9C, are Dynamic Vapor Sorption (DVS) spectra of samplebatches, P1, P2, and P4 of compound S-1, respectively. 9A is a DVS ofform A. 9B is a DVS of form A. 9C is a DVS of form B′.

FIG. 10 demonstrates XRPD spectra of the compound obtained after varyingthe S-1 concentration in given solvents, varying the solvents, or acombination thereof. A—demonstrates XRPD spectra after compound S-1,Form A, suspended in n-heptane, 108 mg/2.0 mL. B—demonstrates XRPDspectra after compound S-1, Form B′, suspended in ethylacetate+n-heptane 1:2 (v/v), 81 mg/1.7 mL. C—demonstrates XRPD spectraafter compound S-1, Form B′ suspended in ethyl acetate+n-pentane 1:2(v/v), 101 mg/1.0 mL. D—demonstrates XRPD spectra after compound S-1Form A, suspended in ethyl acetate+n-pentane 1:2 (v/v), 128 mg/2.0 mL.E—demonstrates XRPD spectra after compound S-1 Form A, suspended inethyl acetate+n-pentane 1:2 (v/v), 112 mg/2.0 mL. F—demonstrates XRPDspectra after compound S-1 Form A, suspended in methyl acetate+n-pentane1:2 (v/v), 126 mg/2.0 mL.

FIG. 11 shows the XRPD pattern representing the results of vapordiffusion experiments conducted with compound S-1. A—demonstrates XRPDspectra of compound S-1 in toluene and n-hexane at 23° C. for 2 days.B—shows a superimposed spectra of XRPD of batch P1 (Form A) and the XRPDobtained in FIG. 11A. C—demonstrates XRPD spectra obtained for compoundS-1 in acetic acid and water at 23° C. for 7 days. D—shows asuperimposed spectra of XRPD of batch P1 (Form A) and the XRPD obtainedin FIG. 11B.

FIG. 12 shows the XRPD pattern representing the results of evaporationexperiment wherein solutions of compounds were dried at room temperature(dry N₂ flow) without stifling. 12A—demonstrates XRPD pattern obtainedof compound S-1 (batch P1) in ethyl-acetate solution. 12B—demonstrates asuperimposed spectra of XRPD of batch P1 (Form A) and the XRPD obtainedin FIG. 12A. 12C—demonstrates XRPD pattern obtained of compound S-1(batch P1) from THF, to provide form C. 12D—demonstrate XRPD patterns ofa mixture of form A (red, top) and form C (blue, bottom), as presentedin FIG. 12C.

FIG. 13 shows the XRPD spectra representing the results ofrecrystallization from solution experiment wherein compound S-1 wasdissolved in different solvent system at room temperature and cooled to+5° C. or to −20° C. 13A—demonstrates XRPD spectra obtained of compoundS-1 (batch P1) in ethylacetate+n-heptane 1:1 (v/v). 13B—shows asuperimposed spectra of XRPD of batch P1 (Form A) and the XRPD obtainedin FIG. 13A. 13C—demonstrates XRPD spectra obtained of compound S-1(batch P1) in acetonitrile+toluene 1:3 v/v. 13D—shows a superimposedspectra of XRPD of batch P1 (Form A) and the XRPD obtained in FIG. 13B.

FIG. 14 shows the XRPD spectra representing the results of freeze dryingexperiment. 14A—demonstrates XRPD spectra obtained of compound S-1(batch P-1) in 1-4-dioxane and cooled to −50° C. 14B—shows asuperimposed spectra of XRPD of batch P1 (Form A) and the XRPD obtainedin FIG. 14A.

FIG. 15 demonstrates a DSC thermogram representing the results of adrying experiment when compound S-1 (batch P4) was dried overnight in adry N₂ atmosphere. The asterisk indicates a settling effect, an artifactof the machinery used.

FIG. 16 demonstrates XRPD spectra representing the results of relativestability experiments wherein suspension experiments were carried outwith mixtures of batches of S-1. 16A—demonstrates XRPD spectra obtainedfrom a mixture of batches of compound S-1 (P1, P18, P24, P30, P37 andP38, all batches have a XRPD characteristics of Form A) inethylacetate+n-heptane 1:2 (v/v) 130 mg/2.0 mL. 16B shows a superimposedspectra of XRPD of batch P1 (Form A) and the XRPD obtained in FIG. 16A.16C—demonstrates XRPD spectra obtained from a mixture of batches ofcompound S-1 (P1 and P52 where batch P1 is Form A and P52 is Form A+C)in ethylacetate+n-heptane 1:2 (v/v); (81+64) mg/2.0 mL. 16D shows asuperimposed spectra of XRPD of batch P1 (Form A) and the XRPD obtainedin FIG. 16B.

FIG. 17 provides a DSC thermogram and XRPD pattern, representing theresults of water vapor sorption where S-1 (batch P1) was stored in aglass tube under 96% r.h (relative humidity) at room temperature.17A—demonstrates the DSC results obtained for compound S-1 batch P1 withno solvent after 11 weeks. 17B—demonstrates XRPD of compound S-1 batchP1 (form A) in water after 19 h at 37° C., resulting in formation ofform B′. 17C—demonstrates XRPD of compound S-1 batch P1 (form A) inacetic acid+water 1:2 (v/v) after 20 h at 23° C. 17D—shows a DSCthermogram of heating a sample of form A (black), cooling of the sampleafter melting (grey) and reheating of the sample (white). Heating rateswere 10° C./min while the cooling rate was 1° C./min. Heating form Abeyond the melting temperature produces B″ which doesn't revert to Aeven when the sample is cooled back down to ambient temperature. 17E—1°C./min DSC runs of form A (grey), B″ (black), mixture of A and D (white)and mixture of B″ and D (dark grey). A and B″ can undergocrystallization to D but only in the presence of D to act as seeds forcrystallization. 17F—DSC graphs for form A stored at ambienttemperature/100% RH for 7 days (light grey), 50° C./0% RH for 7 days(dark grey), and 50° C./75% RH for 6 hours (white) along with the DSCgraph of the original sample (black). 17G—(a) DSC graphs of polymorph Aseeded with form D and stored at 50° C./75% RH. (b) DSC graphs of form Aseeded with form D and stored at 50° C. in water.

FIG. 18 demonstrates XRPD patterns of a superimposed spectra of XRPD ofform A (top) and form D (bottom) of compound S-1.

FIG. 19 demonstrates a DSC thermograms of forms A and D.

FIG. 20 Thermogravimetric analysis (TGA) graph of the toluene solvate(red) and form D (black).

DETAILED DESCRIPTION OF THE INVENTION

In some embodiments, the present invention provides solid forms of (R)or(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2-methylpropanamideand processes of preparation of the same. This invention also providespharmaceutical compositions comprising the solid forms of (R) or(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2-methylpropanamide, and uses thereof.

(R) or(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2-methylpropanamideare androgen receptor targeting agents (ARTA), which demonstrateandrogenic and anabolic activity. In some embodiments, the methylpropionamides as herein described are selective androgen receptormodulators (SARM), which in some embodiments are useful for a) malecontraception; b) treatment of a variety of hormone-related conditions,for example conditions associated with Androgen Decline in Aging Male(ADAM), such as fatigue, depression, decreased libido, sexualdysfunction, erectile dysfunction, hypogonadism, osteoporosis, hairloss, anemia, obesity, sarcopenia, osteopenia, osteoporosis, benignprostate hyperplasia, alterations in mood and cognition and prostatecancer; c) treatment of conditions associated with Androgen Decline inFemale (ADIF), such as sexual dysfunction, decreased sexual libido,hypogonadism, sarcopenia, osteopenia, osteoporosis, alterations incognition and mood, depression, anemia, hair loss, obesity,endometriosis, breast cancer, uterine cancer and ovarian cancer; d)treatment and/or prevention of chronic muscular wasting; e) decreasingthe incidence of, halting or causing a regression of prostate cancer; f)oral androgen relacement and/or other clinical therapeutic and/ordiagnostic areas.

In some embodiments, this invention provides polymorphic solid forms of(R) or(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2-methylpropanamidecompounds of this invention. In one embodiment the term “polymorph”refers to a specific form of the SARM compounds of this invention, forexample, polymorphs may represent crystalline forms that can vary inpharmaceutically relevant physical properties between one form andanother, for example under different crystallization conditions,environmental conditions, hygroscopic activity of the compounds, etc.

In one embodiment, this invention provides, a crystalline form of (R) or(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2-methylpropanamidecompound.

In one embodiment, this invention provides, a crystalline form ofanhydrous (R) or(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2-methylpropanamidecompound.

In one embodiment, this invention provides, a crystalline form ofanhydrous(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2-methylpropanamidecompound.

In another embodiment, the crystalline form of(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2-methylpropanamide(compound S-1), is characterized by:

-   -   a. an X-Ray Powder diffraction pattern comprising peaks at °2θ        (d value Å) angles of about 5.6 (15.9), 7.5 (11.8), 8.6 (10.3),        9.9 (8.9), 12.4 (7.1), 15.0 (5.9), 16.7 (5.3), 17.3 (5.1), 18.0        (4.9), 18.5 (4.8), 19.3 (4.6), 19.8 (4.5), 20.6 (4.3), 21.8        (4.1), 22.3 (4.0), 23.4 (3.8), 23.9 (3.7), 24.6 (3.6), 24.9        (3.6), 25.4 (3.5), 26.0 (3.4), 26.5 (3.4), 27.8 (3.2); and    -   b. a melting point of about 80° C.

According to this aspect and in another embodiment, such a crystallineform of compound S-1, having all or part of the characteristics listedin (a) and (b) is referred to herein as crystalline Form A.

In another embodiment, the solubility of Form A in water is between20-30 mg/L at 22° C. In another embodiment, the solubility of Form A inwater is between 23-27 mg/L at 22° C.

In one embodiment, this invention provides a crystalline form of an(R)—N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2-methylpropanamide(compound R-1), wherein said crystalline form is obtained by methodssimilar to that of the S isomer, as described herein. In someembodiments, such a crystalline form of compound R-1, is structurallyrelated and/or possesses similar characteristics to that of compoundS-1.

In one embodiment this invention provides a paracrystalline (R) or(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2-methylpropanamidecompound.

In one embodiment this invention provides a paracrystalline(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2-methylpropanamidecompound.

In one embodiment, the paracrystalline form of(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2-methylpropanamide(compound S-1) is characterized by:

-   -   a. an X-Ray Powder diffraction pattern displaying a broad halo        with two harmonic peaks between 15-25 °2θ and    -   b. a glass transition point of about 55° C.

According to this aspect and in another embodiment, such aparacrystalline form of compound S-1, having all or part of thecharacteristics listed in (a) and (b) is referred herein asparacrystalline form B′.

In one embodiment the term “paracrystalline” refers to the state ofmaterial exhibiting short-range order without long-range order such asliquid crystals or other type of lamellar structures. In one embodiment,the paracrystalline form is a liquid crystal. In another embodiment, theForm B′ of compound S-1 is a paracrystalline. In another embodiment,form A of S-1 may convert in whole or in part to paracrystalline Form B′of S-1.

In another embodiment, the solubility of Form B′ in water is between20-30 mg/L at 22° C. In another embodiment, the solubility of Form B′ inwater is between 23-27 mg/L at 22° C.

In one embodiment, this invention provides an paracrystalline form B″ of(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2-methylpropanamide,characterized by:

-   -   a. an X-Ray Powder diffraction pattern displaying a broad halo        with two harmonic peaks between 15-25°2θ and    -   b. a glass transition point of about 55° C.

In one embodiment, this invention provides a crystalline Form C of(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2-methylpropanamidecharacterized by:

-   -   a. an X-Ray Powder diffraction pattern comprising unique peaks        at °2θ (d value Å) angles of about 6.9 (12.8), 9.5 (9.3), 13.5        (6.6), 16.0 (5.6), 22.8 (3.9).

In another embodiment, crystalline Form C of compound S-1 is obtained asa mixture of Form A and C, by evaporating A out of THF.

In one embodiment, this invention provides a crystalline Form D of(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2-methylpropanamidecharacterized by:

-   -   a. an X-Ray powder diffraction pattern comprising unique peaks        at °2θ (d value Å) angles of about 4.4 (19.9), 8.5 (10.4), 8.8        (10.0), 11.3 (7.8), 12.7 (6.9), 13.8 (6.4), 14.4 (6.1), 14.6        (6.0), 15.1 (5.8), 16.1 (5.5), 16.6 (5.3), 16.9 (5.2), 18.0        (4.9), 18.7 (4.7), 19.0 (4.6), 19.4 (4.55), 20.8 (4.25), 22.1        (4.0), 22.7 (3.9), 23.1 (3.8), 23.4 (3.8), 24.7 (3.6), 24.9        (3.56), 25.3 (3.51), 27.8 (3.2), 29.3 (3.0); and    -   b. a melting point of about 130° C.

In another embodiment, crystalline Form D of compound S-1 is stable at50° C./75% RH (Relative Humidity) as well as the other conditions ofambient/75% RH, ambient/100% RH, 30° C./75% RH and 50° C./0% RH.

In another embodiment the characteristics of the different solid formsof S-1 are presented in Example 2 and FIGS. 4-20.

Solid forms of this invention can be analysed by any method known in theart for example and in one embodiment, X-ray powder diffraction. Inanother embodiment analysis of the solid forms of this invention maycomprise Raman Spectroscopy. In another embodiment analysis of the solidforms of this invention may comprise TG-FTIR (thermo gravimetric fouriertransform infrared). In another embodiment analysis of the solid formsof this invention may comprise FT-Raman (fourier transform-Raman). Inanother embodiment analysis of the solid forms of this invention maycomprise DSC (differential scanning calorimetry). In another embodimentanalysis of the solid forms of this invention may comprise DVS (dynamicvapor sorption). In another embodiment analysis of the solid forms ofthis invention may comprise SEM (Scanning electron microscopy).

In one embodiment, this invention provides a polymorphic mixturecomprising crystalline forms A and B′ in a ratio of between about 95:5to 85:15, respectively. In another embodiment, the ratio is betweenabout 85:15 to 75:25, respectively. In another embodiment, the ratio isbetween about 75:25 to 65:35, respectively. In another embodiment, theratio is between about 95:5 to 90:10, respectively. In anotherembodiment, the ratio is between about 90:10 to 85:15, respectively. Inanother embodiment, the ratio is between about 97:3 to 93:7,respectively. In another embodiment, the ratio is between about 85:15 to80:20. In another embodiment, the ratio is between about 70:20 to 60:20.In another embodiment, the ratio is 50:50, respectively.

In one embodiment, this invention provides a polymorphic mixturecomprising crystalline forms A, B′ and C in a ratio of between about90:5:5 to 80:10:10, respectively. In another embodiment, the ratio isbetween about 80:10:10 to 75:15:10, respectively. In another embodiment,the ratio is between about 95:3:2 to 90:7:3, respectively. In anotherembodiment, the ratio is between about 75:15:10 to 65:20:15. In anotherembodiment, the ratio is between about 70:20:10 to 60:20:20.

In one embodiment, this invention provides a polymorphic mixturecomprising crystalline forms A, B′ and D in a ratio of between about5:5:90 to 10:10:80, respectively. In another embodiment, the ratio isbetween about 10:10:80 to 10:15:75, respectively. In another embodiment,the ratio is between about 2:3:95 to 3:7:90, respectively. In anotherembodiment, the ratio is between about 10:15:75 to 15:20:65. In anotherembodiment, the ratio is between about 10:20:70 to 20:20:60.

In one embodiment, this invention provides a polymorphic mixturecomprising crystalline forms A and C in a ratio of between about 98:2 to95:5, respectively. In one embodiment, this invention provides apolymorphic mixture comprising crystalline forms A and C in a ratio ofbetween about 95:5 to 90:10, respectively. In one embodiment, thisinvention provides a polymorphic mixture comprising crystalline forms Aand C in a ratio of between about 90:10 to 85:15, respectively. In oneembodiment, this invention provides a polymorphic mixture comprisingcrystalline forms A, and C in a ratio of between about 85:15 to 80:20,respectively. In one embodiment, this invention provides a polymorphicmixture comprising crystalline forms A, and C in a ratio of about 50:50,respectively.

In one embodiment, this invention provides a polymorphic mixturecomprising crystalline forms A and D in a ratio of between about 2:98 to5:95, respectively. In one embodiment, this invention provides apolymorphic mixture comprising crystalline forms A and D in a ratio ofbetween about 5:95 to 10:90, respectively. In one embodiment, thisinvention provides a polymorphic mixture comprising crystalline forms Aand D in a ratio of between about 10:90 to 15:85, respectively. In oneembodiment, this invention provides a polymorphic mixture comprisingcrystalline forms A, and D in a ratio of between about 15:85 to 20:80,respectively. In one embodiment, this invention provides a polymorphicmixture comprising crystalline forms A, and D in a ratio of about 50:50,respectively.

In one embodiment, this invention provides a polymorphic mixturecomprising crystalline forms B′ and D in a ratio of between about 2:98to 5:95, respectively. In one embodiment, this invention provides apolymorphic mixture comprising crystalline forms B′ and D in a ratio ofbetween about 5:95 to 10:90, respectively. In one embodiment, thisinvention provides a polymorphic mixture comprising crystalline forms B′and D in a ratio of between about 10:90 to 15:85, respectively. In oneembodiment, this invention provides a polymorphic mixture comprisingcrystalline forms B′, and D in a ratio of between about 15:85 to 20:80,respectively. In one embodiment, this invention provides a polymorphicmixture comprising crystalline forms B′, and D in a ratio of about50:50, respectively.

In one embodiment, this invention provides a polymorphic mixturecomprising crystalline forms B′ and C in a ratio of between about 98:2to 95:5, respectively. In one embodiment, this invention provides apolymorphic mixture comprising crystalline forms B′ and C in a ratio ofbetween about 95:5 to 90:10, respectively. In one embodiment, thisinvention provides a polymorphic mixture comprising crystalline forms B′and C in a ratio of between about 90:10 to 85:15, respectively. In oneembodiment, this invention provides a polymorphic mixture comprisingcrystalline forms B′ and C in a ratio of between about 85:15 to 80:20,respectively. In one embodiment, this invention provides a polymorphicmixture comprising crystalline forms B′ and C in a ratio of about 50:50,respectively.

In another embodiment, the ratio between crystalline form A tocrystalline form B′ is between about 95:5 to 85:15. In anotherembodiment, the ratio between crystalline form A to crystalline form B′is between about 98:2 to 95:5. In another embodiment, the ratio betweencrystalline form A to crystalline form B′ is between about 85:15 to75:25. In another embodiment, the ratio between crystalline form A tocrystalline form B′ is between about 75:25 to 65:35 respectively.

In one embodiment a sample of(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2-methylpropanamidemay comprise a mixture of solid form A, B′, B″, C and D. In anotherembodiment the percentage of several solid forms in a sample (forexample the percentage of solid form A and B in a sample) can bedetermined by running a Modulated DSC (Differential Scanningcalorimetry) at a heating rate of 3° C./min from 10° C. to 130° C.,followed by linear integration of the solid form A and/or solid form Bto obtain the enthalpy of each.

In one embodiment the solid form of a SARM compound can influence itsbioavailability, stability, processability and ease of manufacture anduses thereof are to be considered part of this invention.

In one embodiment, this invention provides a process for the preparationof a crystalline form of (R) or(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2-methylpropanamidecomprising dissolving amorphous (R) or(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2-methylpropanamidein at least one organic solvent at a temperature of between about −20°C. to +30° C. under conditions permissive to crystallization, therebyobtaining the crystalline form.

In one embodiment, this invention provides a process for the preparationof a crystalline form A of(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2-methylpropanamidecomprising dissolving amorphous(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2-methylpropanamidein at least one organic solvent at a temperature of between about −20°C. to +30° C. under conditions permissive to crystallization, therebyobtaining the crystalline form.

In another embodiment, the temperature for crystallization of(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2-methylpropanamide,is about 5° C. In another embodiment, the temperature is of about −20°C. In another embodiment, the temperature is of about 20° C. In anotherembodiment, the temperature is between about 20 to 50° C. In anotherembodiment, the temperature is about −10 to 0° C. In another embodiment,the temperature is about 0 to 5° C. In another embodiment, thetemperature is about −10 to −20° C.

In another embodiment, form A of(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2-methylpropanamide(compound S-1) is prepared by crystallization from an organic solventcomprising a mixture of solvents. In another embodiment the mixturecomprises two solvents in a 1:2 v/v ratio, respectively. In anotherembodiment the mixture comprises two solvents in a 1:3 v/v ratio,respectively. In another embodiment the mixture comprises two solventsin a 1:4 v/v ratio, respectively. In another embodiment the mixturecomprises ethyl formate and pentane in a 1:2 v/v ratio, respectively. Inanother embodiment, the mixture comprises methyl acetate and pentane ina 1:2 v/v ratio, respectively. In another embodiment the mixturecomprises ethylacetate and n-hexane. In another embodiment the mixturecomprises toluene and n-hexane. In another embodiment the mixturecomprises dichloromethane and n-hexane. In another embodiment themixture comprises acetic acid and water in a 1:2 v/v ratio. In anotherembodiment, form A is prepared by crystallization from asolvent/antisolvent mixture at ambient temperature. In anotherembodiment, ethyl acetate, ethanol, dichloromethane or acetonitrile arethe solvents and n-hexane, n-pentane, n-heptane and cyclohexane etc. areused as antisolvents. In another embodiment the solvent/antisolventratios are between 1:2 and 1:3.

In another embodiment, the crystalline form A of compound S-1 isprepared by forming a suspension of a paracrystalline form of compoundof formula S-1 in a solvent/antisolvent mixture. In another embodimentsolid form A is prepared by forming a suspension of a paracrystallineform of compound of formula S-1 in ethylacetate and heptane mixture in a1:2 v/v ratio, respectively. In another embodiment, solid form A isprepared by forming a suspension of a paracrystalline form of compoundof formula S-1 in a mixture of ethylacetate and pentane in a 1:2 v/vratio, respectively. In another embodiment, the crystalline form A ofcompound S-1 is prepared by forming a suspension of form B′ in asolvent/antisolvent mixture at concentrations above the saturation limitat 23° C. for several hours followed by drying to obtain form A.

In another embodiment, form D of(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2-methylpropanamide(compound S-1) is prepared by crystallization from solvent/antisolventmixture at 50° C. using ethyl acetate and cyclohexane as the solvent andantisolvents, respectively. In another embodiment, form D is preparedfrom other polymorphic forms by “seeding” the sample with a small amountof D and storing it at 110° C./0% RH for 7 days or at 50° C. in waterfor 24 hours followed by drying. In another embodiment, heating forms Aand/or B″ to 110° C. in the presence of D causes the A and B″ forms torearrange into form D. In another embodiment, form D in the presence ofmoisture acts as the seed for the crystallization process and drives thetransformation of forms A and B′ into D.

In another embodiment, FIG. 17G shows the time evolution of polymorph Aseeded with a small amount of D at 50° C./75% RH. The amount ofpolymorph D initially added to the sample is very small that it isn'tdetectable by the DSC with heating rate of 10° C./min. After 24 hours,most of the polymorph form A has been converted to B′ but a small amountof sample has also been converted to D and the amount of sample in Dincreases over time. The transformation process is speeded up in FIG.17G by storing the sample in water at 50° C. Form A has been convertedto both B′ and D after 6 hours but the sample is predominantly in form Dby 24 hours.

In one embodiment this invention provides a process for the preparationof paracrystalline (R) or(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2-methylpropanamidecomprising stifling a suspension of a crystalline form of (R) or(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2-methylpropanamidein water at ambient temperature of about 20-30° C. for at least 0.5hours, to obtain a paracrystalline compound.

In one embodiment this invention provides a process for the preparationof paracrystalline form B′ of(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2-methylpropanamidecomprising stifling a suspension of a crystalline form of(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2-methylpropanamidein water at ambient temperature of about 20-30° C. for at least 0.5hours, to obtain a paracrystalline compound.

In one embodiment this invention provides a process for the preparationof paracrystalline form B′ of(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2-methylpropanamidecomprising stirring a suspension of a crystalline form A of(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2-methylpropanamidein water at ambient temperature of about 20-30° C. for at least 0.5hours, to obtain a paracrystalline compound. In another embodiment,paracrystalline form B′ is prepared by stifling a suspension ofcrystalline form A at 50° C. in water for 24 h. In another embodimentparacrystalline form B′ is prepared by stifling a suspension ofcrystalline form A at 37° C. overnight to obtain paracrystalline formB′.

In one embodiment solid form B′ of(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2-methylpropanamideis prepared by storage of solid form A at 40° C. and 75% relativehumidity (r.h.) for 1-2 h. In another embodiment, solid form A is storedat 40° C. and 75% r.h. for 2-4 h. In another embodiment, solid form A isstored at 40° C. and 75% r.h. for 4-10 h. In another embodiment, solidform A is stored at 40° C. and 75% r.h. for 10-15 h. In anotherembodiment, solid form A is stored at 40° C. and 75% r.h. for 15-24 h.

In another embodiment, solid form A is stored at 40° C. and 75% r.h. for24 h. In another embodiment, solid form A is stored at 40° C. and 75%r.h. for 30 days.

In one embodiment solid form B′ of(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2-methylpropanamideis prepared by storage of solid form A at 40° C. and 75% relativehumidity (r.h.). In another embodiment, solid form A is stored at atemperature range of about of 30-40° C. and relative humidity range ofabout 50-75%. In another embodiment, solid form A is stored at atemperature range of about of 40-50° C. and a relative humidity of about60-80%. In another embodiment, solid form A is stored at a temperaturerange of about 40-50° C. and a relative humidity of about 60-80%.

In one embodiment, form B′ is assigned as a lyotropic liquid crystallineform due to its solvent mediated formation.

In one embodiment liquid crystalline form B″ of(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2-methylpropanamideis prepared by melting or heating solid form A of(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2-methylpropanamideto 80° C. followed by cooling.

In one embodiment form B″ of(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2-methylpropanamideis prepared by melting or heating to 130° C. solid form D of(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2-methylpropanamidefollowed by cooling.

In one embodiment, evaporation of(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2-methylpropanamidefrom solvents such as ethanol without an antisolvent yield form B″.

In one embodiment, form B″ is assigned as a thermotropic liquidcrystalline form from its thermal method of preparation.

In one embodiment this invention provides a process for the preparationof solid form C of(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2-methylpropanamidecomprising dissolving crystalline form A of(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2-methylpropanamidein THF, followed by evaporation to obtain solid form C.

In another embodiment, form C is obtained as a mixture with form A.

In one embodiment this invention provides a process for the preparationof toluene solvate solid form of(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2-methylpropanamidecomprising using any solvent/antisolvent crystallization method thatuses toluene as the antisolvent.

In another embodiment, the toluene solvate solid form has a meltingpoint about 100° C. with the enthalpy of melting 70±5 J/g.

In another embodiment, thermogravimetric analysis (TGA) graph of thetoluene solvate in FIG. 20 shows that the toluene content in the solvateis about 7% which corresponds to one toluene molecule for every threemolecules of S-1. In another embodiment the toluene molecules resideinside the unit cell structure rather than in channels or layers outsidethe lattice. In another embodiment, the toluene solvate solid form isthe most stable form in toluene.

In some embodiments, crystalline forms of the SARMs of this inventioncomprise alteration of a given crystalline form to one structurallysimilar, yet not identical to the original form. In one embodiment, suchchanges in crystalline forms may produce one that is more structurallystable than the original form. In some embodiments, the crystallineforms of this invention comprise altered crystalline forms, as well asoriginal forms, in a single preparation. In some embodiments, suchaltered crystalline forms may comprise a small percentage of the wholeSARM compound preparation, for example, up to 1%, or in anotherembodiment, up to 5%, or up to 10%, or up to 15%, or up to 25% of thepreparation. In another embodiment, such altered forms may comprise themajority of the SARM compound preparation and may comprise 55%, or inanother embodiment, 65%, or in another embodiment, 75%, or 80%, or 85%,or 90%, or 95% or up to 100% of the SARM compound preparation. In oneembodiment, the favorable crystalline form is thermodynamicallyfavorable. In another embodiment the crystalline favorable form is aresult of a change in humidity. In another embodiment the crystallinefavorable form is a result of a change in temperature. In anotherembodiment the crystalline favorable form is a result of a change insolvents.

In some embodiments, the process for the preparation of polymorph of (R)or(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2-methylpropanamidecompounds yield various crystalline forms. In one embodiment the processyields a mixture of crystalline/paracrystalline forms A, B′, C and D. Inone embodiment the process yields a mixture ofcrystalline/paracrystalline forms A, B′, B″, C and D. In anotherembodiment, the process yields a mixture of crystalline forms A and C.In another embodiment, the process yields a mixture ofcrystalline/paracrystalline forms A and B′. In another embodiment, theprocess yields a mixture of crystalline forms A and D. In anotherembodiment, the process yields a mixture of crystalline/paracrystallineforms B′ and D. In another embodiment, the process yields a mixture ofcrystalline/paracrystalline forms B″ and D. In another embodiment, theprocess yields a mixture of crystalline forms C and D. In anotherembodiment, the process yields a mixture of crystalline/paracrystallineforms B′ and C. In another embodiment, the process yields a mixture ofcrystalline/paracrystalline forms A and B″. In another embodiment, theprocess yields a mixture of paracrystalline forms B′ and B″. In anotherembodiment, the process yields a mixture of crystalline/paracrystallineforms C and B″. In another embodiment, the process yields a mixture ofcrystalline/paracrystalline forms A, C and B″. In another embodiment,the process yields a mixture of crystalline/paracrystalline forms A, Dand B″. In another embodiment, the process yields a mixture ofcrystalline/paracrystalline forms B′, B″ and C. In another embodiment,the process yields a mixture of crystalline/paracrystalline forms A, B′and B″. In another embodiment, the process yields a mixture ofcrystalline/paracrystalline forms D, B′ and B″.

In one embodiment, the solid form compounds of this invention are driedfrom solution by vacuum at room temperature, followed by graduallyincreasing the temperature. In another embodiment, the solid formcompounds of this invention are filtered from solution

In one embodiment, the term “ambient temperature” refers to roomtemperature. In another embodiment, the term “ambient temperature”refers to 20-25° C. In another embodiment, “ambient temperature” refersto 25-30° C.

In another embodiment, form D is the most thermodynamically stablepolymorph in both dry conditions and in the presence of water at ambienttemperature up to its melting point of 130° C. In another embodiment,FIG. 19 depicts a differential scanning calorimeter (DSC) thermogram ofform A and form D, where form A melts at about 80° C. and form D meltsat about 130° C. In another embodiment, the enthalpy of melting for formA is 40±5 J/g while the enthalpy of melting for form D is 75±5 J/g.

In another embodiment form A is stable in its A form for at least 7 daysunder storage conditions of ambient temperature/75% RH (RelativeHumidity), ambient temperature/100% RH, 30° C./75% RH and 50° C./0% RH.In another embodiment, form A converts to B′ when stored at 50° C./75%RH. In another embodiment, form A converts to B′when stored at 40°C./75% RH within one month. In another embodiment form A stored at 25°C./60% RH and 30° C./65% RH is stable through 36 months and 9 monthsrespectively.

In one embodiment, (R) or(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2-methylpropanamideare prepared by chiral synthesis.

In one embodiment, the(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2-methylpropanamidemay be prepared by a process according to the following syntheticscheme:

In one embodiment, the process described in the above scheme comprisesreacting the acylanilide in step 5 with the cyanophenol, and suchreaction may be conducted in the presence of potassium carbonate, sodiumcarbonate, or cesium carbonate. In one embodiment, reaction in thepresence of potassium carbonate unexpectedly results in a product withfewer impurities as compared to a reaction conducted in the presence ofcesium carbonate. This represents an improved and more efficientsynthetic process for producing an end product, minimizing the need foradditional purification steps. This finding is also advantageous to theproduction of other compounds such as 6, 9, 12, and 14 below.

In one embodiment, this invention provides a process for preparing(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2-methylpropanamide,said process comprising the steps of:

-   -   a) preparing a carboxylic acid of formula 1 by ring opening of a        cyclic compound of formula 2 in the presence of HBr

-   -   b) reacting an amine of formula 3:

-   -   with the carboxylic acid of formula 2 in the presence of a        coupling reagent, to produce an amide of formula 4

-   -    and    -   c) reacting the amide of formula 4 with a compound of formula 5:

-   -   wherein step (c) is carried out in the presence of potassium        carbonate and tetrahydrofuran.

In one embodiment, this invention provides a process for preparing acompound of formula 6:

said process comprising the steps of:

-   -   a) preparing a carboxylic acid of formula 1 by ring opening of a        cyclic compound of formula 2 in the presence of HBr

-   -   b) reacting an amine of formula 7:

-   -   with the carboxylic acid of formula 2 in the presence of a        coupling reagent, to produce an amide of formula 8:

-   -    and    -   c) reacting the amide of formula 8 with a compound of formula 5:

-   -   wherein step (c) is carried out in the presence of potassium        carbonate and tetrahydrofuran.

In one embodiment, this invention provides a process for preparing acompound of formula 9:

said process comprising the steps of:

-   -   a) preparing a carboxylic acid of formula 1 by ring opening of a        cyclic compound of formula 2 in the presence of HBr

-   -   b) reacting an amine of formula 3:

-   -   with the carboxylic acid of formula 2 in the presence of a        coupling reagent, to produce an amide of formula 4

-   -    and    -   c) reacting the amide of formula 4 with a compound of formula        10:

-   -   wherein step (c) is carried out in the presence of potassium        carbonate and tetrahydrofuran.

In one embodiment, this invention provides a process for preparing acompound of formula 12:

said process comprising the steps of:

-   -   a) preparing a carboxylic acid of formula 1 by ring opening of a        cyclic compound of formula 2 in the presence of HBr

-   -   b) reacting an amine of formula 3:

-   -   with the carboxylic acid of formula 2 in the presence of a        coupling reagent, to produce an amide of formula 4

-   -    and    -   c) reacting the amide of formula 4 with a compound of formula        13:

-   -   wherein step (c) is carried out in the presence of potassium        carbonate and tetrahydrofuran.

In one embodiment, this invention provides a process for preparing acompound of formula 14:

-   -   X is O, NH, Se, PR, or NR;    -   T is OH, OR, NHCOCH₃, or NHCOR;    -   Z is NO₂, CN, COOH, COR, NHCOR or CONHR;    -   Y is CF₃, F, I, Br, Cl, CN, CR₃ or SnR₃;    -   Q is alkyl, halogen, CF₃, CN, CR₃, SnR₃, NR₂, NHCOCH₃, NHCOCF₃,        NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH₃, NHCSCF₃, NHCSR        NHSO₂CH₃, NHSO₂R, OR, COR, OCOR, OSO₂R, SO₂R, SR; or Q together        with the benzene ring to which it is attached is a fused ring        system represented by structure A, B or C:

-   -   R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH₂F, CHF₂,        CF₃, CF₂CF₃, aryl, phenyl, halogen, alkenyl or OH; and    -   R₁ is CH₃, CH₂F, CHF₂, CF₃, CH₂CH₃, or CF₂CF₃; said process        comprising the steps of:    -   a) preparing a carboxylic acid of formula 15 by ring opening of        a cyclic compound of formula 16 in the presence of HBr

-   -   wherein L, R₁ and T are as defined above, and T₁ is O or NH;    -   b) reacting an amine of formula 17:

-   -   wherein Z and Y are as defined above, with the carboxylic acid        of formula 17 in the presence of a coupling reagent, to produce        an amide of formula 18

-   -    and    -   c) coupling the amide of formula II with a compound of formula        19:

wherein Q and X are as defined above and wherein step (c) is carried outin the presence of potassium carbonate and tetrahydrofuran.

In one embodiment, crystalline and paracrystalline forms of thisinvention are prepared by any process which may yield the same, such as,but not limited to those exemplified herein, as will be appreciated byone skilled in the art. In one embodiment, such a process will utilize astarting material for the preparation of crystalline and paracrystallineforms of this invention, which in turn, in some embodiments is preparedaccording to the method schematically depicted hereinabove. In someembodiments, preparing the starting material comprises specific reactionof the amide of formula 4 with a compound of formula 5 in the presenceof potassium carbonate and a polar solvent, such as for example and insome embodiments, tetrahydrofuran, results in the production of a highlypure preparation, which in turn may enhance the rate of crystallization.In some embodiments, use of the pure preparation as described herein,depending upon crystallization conditions employed may result in variedratio of crystalline forms obtained. In some embodiments, use of thepure preparation as described herein, depending upon crystallizationconditions employed may result in varied ratio of crystalline forms, andthe rate at which such forms are produced.

In one embodiment, the process further comprises the step of convertingthe selective androgen receptor modulator (SARM) compound (R) or(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2-methylpropanamideto its analog, isomer, polymorph, polymorph form A, paracrystalline formB′, solvate, metabolite, derivative, pharmaceutically acceptable salt,pharmaceutical product, N-oxide, hydrate, hemi-hydrate or anycombination thereof.

In one embodiment, this invention provides a process for preparing ananalog of a selective androgen modulator compound of this invention. Inanother embodiment, this invention provides a process for preparing anisomer of a selective androgen modulator compound of this invention. Inanother embodiment, this invention provides a process for preparing ametabolite of a selective androgen modulator compound of this invention.In another embodiment, this invention provides a process for preparing aderivative of a selective androgen modulator compound of this invention.In another embodiment, this to invention provides a process forpreparing a pharmaceutically acceptable salt of a selective androgenmodulator compound of this invention. In another embodiment, thisinvention provides a process for preparing a pharmaceutical product of aselective androgen modulator compound of this invention. In anotherembodiment, this invention provides a process for preparing an N-oxideof a selective androgen modulator compound of this invention. In anotherembodiment, this invention provides a process for preparing a hydrate ofa selective androgen modulator compound of this invention. In anotherembodiment, this invention provides a process for preparing a polymorphof a selective androgen modulator compound of this invention. In anotherembodiment, this invention provides a process for preparing a polymorphform A as herein described of a selective androgen modulator compound ofthis invention. In another embodiment, this invention provides a processfor preparing a paracrystalline form B′ as herein described of aselective androgen modulator compound of this invention. In anotherembodiment, this invention provides a process for preparing a polymorphform C as herein described of a selective androgen modulator compound ofthis invention. In another embodiment, this invention provides a processfor preparing a polymorph form D as herein described of a selectiveandrogen modulator compound of this invention. In another embodiment,this invention provides a process for preparing a paracrystalline formof a selective androgen modulator compound of this invention. In anotherembodiment, this invention provides a process for preparing a solvate ofa selective androgen modulator compound of this invention. In anotherembodiment, this invention provides a process for preparing acombination of any of an analog, isomer, metabolite, derivative,polymorph, polymorph form A, paracrystalline form B′, paracrystalline,solvate, pharmaceutically acceptable salt, N-oxide and/or hydrates of aselective androgen modulator compound of this invention. In oneembodiment this invention comprises any compound thus prepared.

In one embodiment, the term “isomer” includes, but is not limited to,optical isomers and analogs, structural isomers and analogs,conformational isomers and analogs, and the like.

In one embodiment, the SARMs are the pure (R)-enantiomer. In anotherembodiment, the SARMs are the pure (S) enantiomer. In anotherembodiment, the SARMs are a mixture of the (R) and the (S) enantiomers.In another embodiment, the SARMs are a racemic mixture comprising anequal amount of the (R) and the (S) enantiomers. In one embodiment, theprocess of the present invention further provides a step of convertingthe SARM compound into its optically active isomer.

In one embodiment, separation of the optically-active (R) enantiomer or(S) enantiomer, from the racemic SARM compounds of this inventioncomprises crystallization techniques. In another embodiment, thecrystallization techniques include differential crystallization ofenantiomers. In another embodiment, the crystallization techniquesinclude differential crystallization of diastereomeric salts (tartaricsalts or quinine salts). In another embodiment, the crystallizationtechniques include differential crystallization of chiral auxiliaryderivatives (menthol esters, etc). In another embodiment, separation ofthe optically-active (R) enantiomer or (S) enantiomer, from the racemicSARM compounds of this invention comprises reacting the racemate mixturewith another chiral group, forming of a diastereomeric mixture followedby separation of the diastereomers and removing the additional chiralgroup to obtain pure enantiomers. In another embodiment, separation ofthe optically-active (R) enantiomer or (S) enantiomer, from the racemicSARM compounds of this invention comprises chiral synthesis. In anotherembodiment, separation of the optically-active (R) enantiomer or (S)enantiomer, from the racemic SARM compounds of this invention comprisesbiological resolution. In another embodiment, separation of theoptically-active (R) enantiomer or (S) enantiomer, from the racemic SARMcompounds of this invention comprises enzymatic resolution. In anotherembodiment, separation of the optically-active (R) enantiomer or (S)enantiomer, from the racemic SARM compounds of this invention compriseschromatographic separation using a chiral stationary phase. In anotherembodiment, separation of the optically-active (R) enantiomer or (S)enantiomer, from the racemic SARM compounds of this invention comprisesaffinity chromatography. In another embodiment, separation of theoptically-active (R) enantiomer or (S) enantiomer, from the racemic SARMcompounds of this invention comprises capillary electrophoresis. Inanother embodiment, separation of the optically-active (R) enantiomer or(S) enantiomer, from the racemic SARM compounds of this inventioncomprises forming an ester group of the hydroxyl group of the chiralcarbon with an optically-active acid, for example (−)-camphanic acid,separating the diastereomers esters, thus obtained, by fractionalcrystallization or preferably, by flash-chromatography, and thenhydrolyzing each separate ester to the alcohol.

In another embodiment the S-enantiomer of SARM compound of thisinvention can be converted to the R-enantiomer or to its racemate. Inanother embodiment the R-enantiomer of SARM compound of this inventioncan be converted to the S-enantiomer or to its racemate. In oneembodiment, one enantiomer can be converted to the other enantiomer orits racemate by using a chiral reactant, a solvent, a biocatalyst,chiral catalyst, asymmetric hydrogenation, an enzyme, or combinationthereof.

In some embodiments the solid compounds of this invention comprisesolvates. In one embodiment the term “solvate” refers to solventscombined with SARM compounds, for example, a solvate of ethylacetate,which is part of a polymorph structure of the SARM compound. Suchsolvents include ethanol, acetone, ethylacetate, THF, acetonitrile,dichloromethane, 1,4-dioxane, acetic acid, toluene, water, n-heptane,toluene, n-pentane TBME, or any combination thereof.

In another embodiment, the process of the present invention furtherprovides a step of converting the SARM compound into itspharmaceutically acceptable salt. In one embodiment, pharmaceuticallyacceptable salts include salts of amino-substituted compounds withorganic and inorganic acids, for example, citric acid and hydrochloricacid. The invention also includes N-oxides of the amino substituents ofthe compounds described herein. Pharmaceutically acceptable salts canalso be prepared from phenolic compounds by treatment with inorganicbases, for example, sodium hydroxide. Also, esters of the phenoliccompounds can be made with aliphatic and aromatic carboxylic acids, forexample, acetic acid and benzoic acid esters.

The invention includes “pharmaceutically acceptable salts” of thecompounds of this invention, which may be produced, by reaction of acompound of this invention with an acid or base.

Suitable pharmaceutically-acceptable salts of amines of Formula I may beprepared from an inorganic acid or from an organic acid. In oneembodiment, examples of inorganic salts of amines are bisulfates,borates, bromides, chlorides, hemisulfates, hydrobromates,hydrochlorates, 2-hydroxyethylsulfonates (hydroxyethanesulfonates),iodates, iodides, isothionates, nitrate, persulfates, phosphate,sulfates, sulfamates, sulfanilates, sulfonic acids (alkylsulfonates,arylsulfonates, halogen substituted alkylsulfonates, halogen substitutedarylsulfonates), sulfonates and thiocyanates.

In one embodiment, examples of organic salts of amines comprisealiphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic,carboxylic and sulfonic classes of organic acids, examples of which areacetates, arginines, aspartates, ascorbates, adipates, anthranilate,algenate, alkane carboxylates, substituted alkane carboxylates,alginates, to benzenesulfonates, benzoates, bisulfates, butyrates,bicarbonates, bitartrates, carboxilates, citrates, camphorates,camphorsulfonates, cyclohexylsulfamates, cyclopentanepropionates,calcium edetates, camsylates, carbonates, clavulanates, cinnamates,dicarboxylates, digluconates, dodecylsulfonates, dihydrochlorides,decanoates, enanthuates, ethanesulfonates, edetates, edisylates,estolates, esylates, fumarates, formates, fluorides, galacturonates,gluconates, glutamates, glycolates, glucorate, glucoheptanoates,glycerophosphates, gluceptates, glycollylarsanilates, glutarates,glutamate, heptanoates, hexanoates, hydroxymaleates, hydroxycarboxlicacids, hexylresorcinates, hydroxybenzoates, hydroxynaphthoate,hydrofluorate, lactates, lactobionates, laurates, malates, maleates,methylenebis(beta-oxynaphthoate), malonates, mandelates, mesylates,methane sulfonates, methylbromides, methylnitrates, methylsulfonates,monopotassium maleates, mucates, monocarboxylates, mitrates,naphthalenesulfonates, 2-naphthalenesulfonates, nicotinates, napsylates,N-methylglucamines, oxalates, octanoates, oleates, pamoates,phenylacetates, picrates, phenylbenzoates, pivalates, propionates,phthalates, phenylacetate, pectinates, phenylpropionates, palmitates,pantothenates, polygalacturates, pyruvates, quinates, salicylates,succinates, stearates, sulfanilate, subacetates, tartarates,theophyllineacetates, p-toluenesulfonates (tosylates),trifluoroacetates, terephthalates, tannates, teoclates, trihaloacetates,triethiodide, tricarboxylates, undecanoates or valerates.

In one embodiment, examples of inorganic salts of carboxylic acids orphenols comprise ammonium, alkali metals to include lithium, sodium,potassium, cesium; alkaline earth metals to include calcium, magnesium,aluminium; zinc, barium, cholines or quaternary ammoniums.

In another embodiment, examples of organic salts of carboxylic acids orphenols comprise arginine, organic amines to include aliphatic organicamines, alicyclic organic amines, aromatic organic amines, benzathines,t-butylamines, benethamines (N-benzylphenethylamine),dicyclohexylamines, dimethylamines, diethanolamines, ethanolamines,ethylenediamines, hydrabamines, imidazoles, lysines, methylamines,meglamines, N-methyl-D-glucamines, N,N′-dibenzylethylenediamines,nicotinamides, organic amines, ornithines, pyridines, picolinates,piperazines, procain, tris(hydroxymethyl)methylamines, triethylamines,triethanolamines, trimethylamines, tromethamines or ureas.

In one embodiment, the salts may be formed by conventional means, suchas by reacting the free base or free acid form of the product with oneor more equivalents of the appropriate acid or base in a solvent ormedium in which the salt is insoluble or in a solvent such as water,which is removed in vacuo or by freeze drying or by exchanging the ionsof a existing salt for another ion or suitable ion-exchange resin.

In one embodiment, the invention also includes N-oxides of the aminosubstituents of the compounds described herein. Also, esters of thephenolic compounds can be made with aliphatic and aromatic carboxylicacids, for example, acetic acid and benzoic acid esters.

This invention further includes a process for preparing derivatives ofthe SARM compounds. In some embodiments, the term “derivative” includes,but is not limited to, ether derivatives, acid derivatives, amidederivatives, ester derivatives and the like. Methods of preparingderivatives are known to a person skilled in the art. For example, etherderivatives are prepared by coupling of the corresponding alcohols.Amide and ester derivatives are prepared from the correspondingcarboxylic acid by a reaction with amines and alcohols, respectively.

In some embodiments, this invention comprises a process for preparinghydrates of the SARM compounds. In one embodiment the term “hydrate”includes, but is not limited to, hemi-hydrate, monohydrate, dihydrate,trihydrate and the like. Hydrates of the SARM compounds may be preparedby contacting the SARM compound with water under suitable conditions toproduce the hydrate of choice. The term “hemi-hydrate” refers to hydratein which the molecular ratio of water molecules to anhydrous compound is1:2.

This invention further includes a process for preparing pharmaceuticalproducts of the SARM compounds. The term “pharmaceutical product” meansa composition suitable for pharmaceutical use (pharmaceuticalcomposition), as defined herein.

In some embodiments, this invention comprises a process for preparinganalogs of the SARM compounds. In one embodiment the term “analog”refers to a compound with a structure, which is similar, but notidentical to that of the referenced compound. In another embodiment theterm “analog” refers to an isomer or derivative of the SARM compound. Inanother embodiment the term “analog of a SARM compound” of thisinvention refers to a compound having different substituents on each orboth phenyl rings in the compound. In another embodiment, the term“analog” refers to the incorporation of different aromatic rings, forexample pyridyl rings, in place of the one or both benzene rings. Inanother embodiment, the term “analog” refers to the incorporation of asulfur atom instead of each or to both ether and keto groups.

In some embodiments, this invention comprises a metabolite of the SARMcompounds. The term “metabolite” refers, in some embodiments to anysubstance produced from another substance by mimicking or via metabolicprocess. In some embodiment such metabolites can be preparedsynthetically and are active in situ, as they are comparable tonaturally produced metabolites.

In some embodiments, the term “about” refers to an up to 10% variancefrom a specified value, or in some embodiments, an up to 5% variancefrom a specified value, or in some embodiments, an up to 1% variancefrom a specified value. In some embodiments, the term “about” refers toa value falling within a scientifically acceptable error range for thattype of value, which will depend on the qualitative nature of themeasurement obtained given the tools and methodology available.

In some embodiments, the term “unique” as used herein refers to beingthe only one, or in some embodiments, the term “unique” refers to beingwithout a like or equal.

Pharmaceutical Compositions

In one embodiment, this invention provides a composition comprising acrystalline form of anhydrous (R) or(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2-methylpropanamideand a suitable carrier or diluent.

In another embodiment, this invention provides a composition comprisinga crystalline form A of anhydrous(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2-methylpropanamideand a suitable carrier or diluent.

In one embodiment, this invention provides a composition comprising aparacrystalline form of (R) or(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2-methylpropanamideand a suitable carrier or diluent.

In one embodiment, this invention provides a composition comprising aparacrystalline form B′ of(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2-methylpropanamideand a suitable carrier or diluent.

In one embodiment, this invention provides a composition comprising amixture of any solid forms of (R) or(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2-methylpropanamidecompound of this invention and a suitable carrier or diluent.

In another embodiment, this invention provides a composition comprisinga mixture of crystalline and paracrystalline solid forms of (R) or(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2-methylpropanamidecompound and a suitable carrier or diluent.

In another embodiment, this invention provides a composition comprisinga mixture of crystalline form A and paracrystalline solid form B′ of(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2-methylpropanamidecompound and a suitable carrier or diluent.

In one embodiment, this invention encompasses compositions comprisingthe different forms of (R) or(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2-methylpropanamidethey can be in different ratios or a single form per composition, whichpossesses properties useful in the treatment of androgen-relatedconditions described herein. In another embodiment, this inventionencompasses compositions comprising different isomers ofN-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2-methylpropanamide,they can be in different ratios or a single isomer per composition,which possesses properties useful in the treatment of androgen-relatedconditions described herein.

In some embodiments, the phrase, “pharmaceutical composition” refers toa “therapeutically effective amount” of the active ingredient, i.e. theSARM compound, together with a pharmaceutically acceptable carrier ordiluent. In some embodiments, the phrase “therapeutically effectiveamount” refers to an amount which provides a therapeutic effect for agiven condition and administration regimen.

The pharmaceutical compositions containing the SARM agent can beadministered to a subject by any method known to a person skilled in theart, such as parenterally, paracancerally, transmucosally,transdermally, intramuscularly, intravenously, intradermally,subcutaneously, intraperitoneally, intraventricularly, intracranially orintratumorally.

In another embodiment this invention provides, a composition of thesolid forms of this invention and a suitable carrier or diluent.

In one embodiment, the pharmaceutical compositions are administeredorally, and are thus formulated in a form suitable for oraladministration, i.e. as a solid preparation. Suitable solid oralformulations include tablets, capsules, pills, granules, pellets and thelike. In one embodiment of the present invention, the SARM compounds areformulated in a capsule. In accordance with this embodiment, thecompositions of the present invention to comprise in addition to theSARM active compound and the inert carrier or diluent, a hard gelatingcapsule.

Oral formulations containing the present polymorph can comprise anyconventionally used oral forms, including tablets, capsules, buccalforms, troches, or lozenges. Capsules may contain mixtures of thecrystalline form A in the desired percentage together any otherpolymorph(s) of SARM or amorphous SARM. Capsules or tablets of thedesired crystalline form of the desired percentage composition may alsobe combined with mixtures of other active compounds or inert fillersand/or diluents such as the pharmaceutically acceptable starches (e.g.corn, potato or tapioca starch), sugars, artificial sweetening agents,powdered celluloses, such as crystalline and microcrystallinecelluloses, flours, gelatins, gums, etc.

Tablet formulations can be made by conventional compression, wetgranulation, or dry granulation methods and utilize pharmaceuticallyacceptable diluents (fillers), binding agents, lubricants,disintegrants, suspending or stabilizing agents, including, but notlimited to, magnesium stearate, stearic acid, talc, sodium laurylsulfate, microcrystalline cellulose, carboxymethylcellulose calcium,polyvinylpyrrolidone, gelatin, alginic acid, acacia gum, xanthan gum,sodium citrate, complex silicates, calcium carbonate, glycine, dextrin,sucrose, sorbitol, dicalcium phosphate, calcium sulfate, lactose,kaolin, mannitol, sodium chloride, talc, dry starches and powderedsugar. Oral formulations, in some embodiments, utilize standard delay ortime release formulations or spansules.

Example excipient systems suitable for preparing formulations of thepresent polymorph include one or more fillers, disintegrants, andlubricants.

The filler component can be any filler component known in the artincluding, but not limited to, lactose, microcrystalline cellulose,sucrose, mannitol, calcium phosphate, calcium carbonate, powderedcellulose, maltodextrin, sorbitol, starch, or xylitol.

Disintegrants suitable for use in the present formulations can beselected from those known in the art, including pregelatinized starchand sodium starch glycolate. Other useful disintegrants includecroscarmellose sodium, crospovidone, starch, alginic acid, sodiumalginate, clays (e.g. veegum or xanthan gum), cellulose floc, ionexchange resins, or effervescent systems, such as those utilizing foodacids (such as citric acid, tartaric acid, malic acid, fumaric acid,lactic acid, adipic acid, ascorbic acid, aspartic acid, erythorbic acid,glutamic acid, and succinic acid) and an alkaline carbonate component(such as sodium bicarbonate, calcium carbonate, magnesium carbonate,potassium carbonate, ammonium carbonate, etc.). The disintegrant(s)useful herein can comprise from about 4% to about 40% of the compositionby weight, preferably from about 15% to about 35%, more preferably fromabout 20% to about 35%.

The pharmaceutical formulations can also contain an antioxidant or amixture of antioxidants, such as ascorbic acid. Other antioxidants whichcan be used include sodium ascorbate and ascorbyl palmitate, preferablyin conjunction with an amount of ascorbic acid. An example range for theantioxidant(s) is from about 0.5% to about 15% by weight, mostpreferably from about 0.5% to about 5% by weight.

In some embodiments of this invention, the active pharmacologicalagent(s) comprise from about 0.5% to about 20%, by weight, of the finalcomposition, or in some embodiments, from about 1% to about 5%, and thecoating or capsule comprises up to about 8%, by weight, of the finalcomposition.

The formulations described herein can be used in an uncoated ornon-encapsulated solid form. In some embodiments, the pharmacologicalcompositions are optionally coated with a film coating, for example,comprising from about 0.3% to about 8% by weight of the overallcomposition. Film coatings useful with the present formulations areknown in the art and generally consist of a polymer (usually acellulosic type of polymer), a colorant and a plasticizer. Additionalingredients such as wetting agents, sugars, flavors, oils and lubricantsmay be included in film coating formulations to impart certaincharacteristics to the film coat. The compositions and formulationsherein may also be combined and processed as a solid, then placed in acapsule form, such as a gelatin capsule.

In another embodiment, the active compound can be delivered in avesicle, in particular a liposome (see Langer, Science 249:1527-1533(1990); Treat et al., in Liposomes in the Therapy of Infectious Diseaseand Cancer, Lopez-Berestein and Fidler (eds.), Liss, New York, pp.353-365 (1989); Lopez-Berestein, ibid., pp. 317-327; see generallyibid).

As used herein “pharmaceutically acceptable carriers or diluents” arewell known to those skilled in the art. The carrier or diluent may be asolid carrier or diluent for solid formulations.

Solid carriers/diluents include, but are not limited to, a gum, a starch(e.g. corn starch, pregeletanized starch), a sugar (e.g., lactose,mannitol, sucrose, dextrose), a cellulosic material (e.g.microcrystalline cellulose), an acrylate (e.g. polymethylacrylate),calcium carbonate, magnesium oxide, talc, or mixtures thereof.

In addition, the compositions may further comprise binders (e.g. acacia,cornstarch, gelatin, carbomer, ethyl cellulose, guar gum, hydroxypropylcellulose, hydroxypropyl methyl cellulose, povidone), disintegratingagents (e.g. cornstarch, potato starch, alginic acid, silicon dioxide,croscarmelose sodium, crospovidone, guar gum, sodium starch glycolate),buffers (e.g., Tris-HCl, acetate, phosphate) of various pH and ionicstrength, additives such as albumin or gelatin to prevent absorption tosurfaces, detergents (e.g., Tween 20, Tween 80, Pluronic F68, bile acidsalts), protease inhibitors, surfactants (e.g. sodium lauryl sulfate),permeation enhancers, solubilizing agents (e.g., glycerol, polyethyleneglycerol), anti-oxidants (e.g., ascorbic acid, sodium metabisulfite,butylated hydroxyanisole), stabilizers (e.g. hydroxypropyl cellulose,hyroxypropylmethyl cellulose), viscosity increasing agents (e.g.carbomer, colloidal silicon dioxide, ethyl cellulose, guar gum),sweetners (e.g. aspartame, citric acid), preservatives (e.g.,Thimerosal, benzyl alcohol, parabens), lubricants (e.g. stearic acid,magnesium stearate, polyethylene glycol, sodium lauryl sulfate),flow-aids (e.g. colloidal silicon dioxide), plasticizers (e.g. diethylphthalate, triethyl citrate), emulsifiers (e.g. carbomer, hydroxypropylcellulose, sodium lauryl sulfate), polymer coatings (e.g., poloxamers orpoloxamines), coating and film forming agents (e.g. ethyl cellulose,acrylates, polymethacrylates) and/or adjuvants.

In one embodiment, the pharmaceutical compositions provided herein arecontrolled release compositions, i.e. compositions in which the SARMcompound is released over a period of time after administration. Inanother embodiment, the composition is an immediate release composition,i.e. a composition in which all of the SARM compound is releasedimmediately after administration.

In yet another embodiment, the pharmaceutical composition can bedelivered in a controlled release system. For example, the agent may beadministered using liposomes, or other modes of oral administration.

The compositions may also include incorporation of the active materialinto or onto particulate preparations of polymeric compounds such aspolylactic acid, polglycolic acid, hydrogels, etc, or onto liposomes,microemulsions, micelles, unilamellar or multilamellar vesicles,erythrocyte ghosts, or spheroplasts. Such compositions will influencethe physical state, solubility, stability, rate of in vivo release, andrate of in vivo clearance.

The preparation of pharmaceutical compositions which contain an activecomponent is well understood in the art, for example by mixing,granulating, or tablet-forming processes. The active therapeuticingredient is often mixed with excipients which are pharmaceuticallyacceptable and compatible with the active ingredient. For oraladministration, the SARM agents or their physiologically toleratedderivatives such as salts, esters, N-oxides, and the like are mixed withadditives customary for this purpose, such as vehicles, stabilizers, orinert diluents, and converted by customary methods into suitable formsfor administration, such as tablets, coated tablets, hard or softgelatin capsules, aqueous, alcoholic or oily solutions.

An active component can be formulated into the composition asneutralized pharmaceutically acceptable salt forms. Pharmaceuticallyacceptable salts include the acid addition salts (formed with the freeamino groups of the polypeptide or antibody molecule), which are formedwith inorganic acids such as, for example, hydrochloric or phosphoricacids, or such organic acids as acetic, oxalic, tartaric, mandelic, andthe like. Salts formed from the free carboxyl groups can also be derivedfrom inorganic bases such as, for example, sodium, potassium, ammonium,calcium, or ferric hydroxides, and such organic bases as isopropylamine,trimethylamine, 2-ethylamino ethanol, histidine, procaine, and the like.

For use in medicine, the salts of the SARM will be pharmaceuticallyacceptable salts. Other salts may, however, be useful in the preparationof the compounds according to the invention or of their pharmaceuticallyacceptable salts. Suitable pharmaceutically acceptable salts of thecompounds of this invention include acid addition salts which may, forexample, be formed by mixing a solution of the compound according to theinvention with a solution of a pharmaceutically acceptable acid such ashydrochloric acid, sulphuric acid, methanesulphonic acid, fumaric acid,maleic acid, succinic acid, acetic acid, benzoic: acid, oxalic acid,citric acid, tartaric acid, carbonic acid or phosphoric acid.

Biological Activity of Selective Androgen Modulator Compounds

The solid forms and processes for producing the same provided hereinare, in some embodiments, directed to selective androgen receptormodulators (SARMs), which are useful for oral testosterone replacementtherapy, having unexpected in-vivo androgenic and anabolic activity. Insome embodiments, appropriately substituted compounds are effective totreat prostate cancer and useful for imaging of prostate cancer.

As contemplated herein, the appropriately substituted SARM compounds ofthe present invention are useful for a) male contraception; b) treatmentof a variety of hormone-related conditions, for example conditionsassociated with Androgen Decline in Aging Male (ADAM), such as fatigue,depression, decreased libido, sexual dysfunction, erectile dysfunction,hypogonadism, osteoporosis, hair loss, anemia, obesity, sarcopenia,osteopenia, osteoporosis, benign prostate hyperplasia, alterations inmood and cognition and prostate cancer; c) treatment of conditionsassociated with ADIF, such as sexual dysfunction, decreased sexuallibido, hypogonadism, sarcopenia, osteopenia, osteoporosis, alterationsin cognition and mood, depression, anemia, hair loss, obesity,endometriosis, breast cancer, uterine cancer and ovarian cancer; d)treatment and/or prevention of chronic muscular wasting; e) decreasingthe incidence of, halting or causing a regression of prostate cancer; f)oral androgen relacement and/or other clinical therapeutic and/ordiagnostic areas.

As used herein, receptors for extracellular signaling molecules arecollectively referred to as “cell signaling receptors”. Many cellsignaling receptors are transmembrane proteins on a cell surface; whenthey bind an extracellular signaling molecule (i.e., a ligand), theybecome activated so as to generate a cascade of intracellular signalsthat alter the behavior of the cell. In contrast, in some cases, thereceptors are inside the cell and the signaling ligand has to enter thecell to activate them; these signaling molecules therefore must besufficiently small and hydrophobic to diffuse across the plasma membraneof the cell. As used herein, these receptors are collectively referredto as “intracellular cell signaling receptors”.

Steroid hormones are one example of small hydrophobic molecules thatdiffuse directly across the plasma membrane of target cells and bind tointracellular cell signaling receptors. These receptors are structurallyrelated and constitute the intracellular receptor superfamily (orsteroid-hormone receptor superfamily). Steroid hormone receptors includeprogesterone receptors, estrogen receptors, androgen receptors,glucocorticoid receptors, and mineralocorticoid receptors. The presentinvention is particularly directed to androgen receptors.

In addition to ligand binding to the receptors, the receptors can beblocked to prevent ligand binding. When a substance binds to a receptor,the three-dimensional structure of the substance fits into a spacecreated by the three-dimensional structure of the receptor in a ball andsocket configuration.

In one embodiment, the present invention is directed to processes forpreparing solid forms of selective androgen receptor modulator compoundswhich are agonist compounds. Thus, in one embodiment, the SARM compoundsof the present invention are useful in to binding to and activatingsteroidal hormone receptors. In one embodiment, the agonist compound ofthe present invention is an agonist which binds the androgen receptor.In another embodiment, the compound has high affinity for the androgenreceptor. In another embodiment, the agonist compound also has anabolicactivity. In another embodiment, the present invention providesselective androgen modulator compounds which have agonistic and anabolicactivity of a nonsteroidal compound for the androgen receptor.

In one embodiment, the present invention is directed to processes forpreparing solid forms of selective androgen receptor modulator compoundswhich are antagonist compounds. Thus, in one embodiment, the solid formsof the SARM compounds of the present invention are useful in binding toand inactivating steroidal hormone receptors. In another embodiment, thesolid forms of the invention have a high affinity for the androgenreceptor. In another embodiment, the solid forms of this invention alsohave anabolic activity. In another embodiment, the solid forms of theSARM compounds bind irreversibly to the androgen receptor. In anotherembodiment, the solid forms of the SARM compounds are alkylating agents.

In yet another embodiment, the solid forms of the SARM compounds of thepresent invention can be classified as partial AR agonist/antagonists.The solid forms of the SARMs are AR agonists in some tissues, and causeincreased transcription of AR-responsive genes (e.g. muscle anaboliceffect). In other tissues, these compounds serve as inhibitors at the ARto prevent agonistic effects of the native androgens.

Assays to determine whether the compounds of the present invention areAR agonists or antagonists are well known to a person skilled in theart. For example, AR agonistic activity can be determined by monitoringthe ability of the solid forms of the SARM compounds to maintain and/orstimulate the growth of AR containing tissue such as prostate andseminal vesicles, as measured by weight. AR antagonistic activity can bedetermined by monitoring the ability of the SARM compounds to inhibitthe growth of AR containing tissue.

In another embodiment, the solid forms of the SARM compounds bindirreversibly to the androgen receptor of a mammal, for example a human.Thus, in one embodiment, the compounds of the present invention maycontain a functional group (e.g. affinity label) that allows alkylationof the androgen receptor (i.e. covalent bond formation). Thus, in thiscase, the compounds are alkylating agents which bind irreversibly to thereceptor and, accordingly, cannot be displaced by a steroid, such as theendogenous ligands DHT and testosterone. An to “alkylating agent” isdefined herein as an agent which alkylates (forms a covalent bond) witha cellular component, such as DNA, RNA or protein. It is a highlyreactive chemical that introduces alkyl radicals into biologicallyactive molecules and thereby prevents their proper functioning. Thealkylating moiety is an electrophilic group that interacts withnucleophilic moieties in cellular components.

According to one embodiment of the present invention, a method isprovided for binding the solid forms of the SARM compounds of thepresent invention to an androgen receptor by contacting the receptorwith the solid forms of the SARM compound, such as polymorph form A,polymorph form C, polymorph form D, paracrystalline form B′,paracrystalline B″, a solvate thereof, a polymorph thereof, a metabolitethereof, etc., or any combination thereof, under conditions effective tocause the selective androgen receptor modulator compound to bind theandrogen receptor. The binding of the solid forms of the selectiveandrogen receptor modulator compounds to the androgen receptor enablesthe compounds of the present invention to be useful as a malecontraceptive and in a number of hormone therapies. The agonistcompounds bind to and activate the androgen receptor. The antagonistcompounds bind to and inactivate the androgen receptor. Binding of theagonist or antagonist compounds is either reversible or irreversible.

In one embodiment, the solid forms of the SARM compounds of the presentinvention are administered as the sole active ingredient. However, alsoencompassed within the scope of the present invention are methods forhormone therapy, for treating prostate cancer, for delaying theprogression of prostate cancer, and for preventing and/or treating therecurrence of prostate cancer, which comprise administering the solidforms of the SARM compounds in combination with one or more therapeuticagents. These agents include, but are not limited to: LHRH analogs,reversible antiandrogens, antiestrogens, anticancer drugs, 5-alphareductase inhibitors, aromatase inhibitors, progestins, agents actingthrough other nuclear hormone receptors, selective estrogen receptormodulators (SERM), progesterone, estrogen, PDE5 inhibitors, apomorphine,bisphosphonate, and one or more solid forms of the SARMS, for exampleone with AR agonistic activity.

Thus, in one embodiment, the present invention provides compositions andpharmaceutical compositions comprising the solid forms of the selectiveandrogen receptor modulator compound, in combination with an LHRHanalog. In another embodiment, the present invention providescompositions and pharmaceutical compositions comprising the solid formsof the selective androgen receptor modulator compound, in combinationwith a to reversible antiandrogen. In another embodiment, the presentinvention provides compositions and pharmaceutical compositionscomprising the solid forms of the selective androgen receptor modulatorcompound, in combination with an antiestrogen. In another embodiment,the present invention provides compositions and pharmaceuticalcompositions comprising the solid forms of the selective androgenreceptor modulator compound, in combination with an anticancer drug. Inanother embodiment, the present invention provides compositions andpharmaceutical compositions comprising the solid forms of the selectiveandrogen receptor modulator compound, in combination with a 5-alphareductase inhibitor. In another embodiment, the present inventionprovides compositions and pharmaceutical compositions comprising thesolid forms of the selective androgen receptor modulator compound, incombination with an aromatase inhibitor. In another embodiment, thepresent invention provides compositions and pharmaceutical compositionscomprising the solid forms of the selective androgen receptor modulatorcompound, in combination with a progestin. In another embodiment, thepresent invention provides compositions and pharmaceutical compositionscomprising the solid forms of the selective androgen receptor modulatorcompound, in combination with an agent acting through other nuclearhormone receptors. In another embodiment, the present invention providescompositions and pharmaceutical compositions comprising the solid formsof the selective androgen receptor modulator compound, in combinationwith a selective estrogen receptor modulators (SERM). In anotherembodiment, the present invention provides compositions andpharmaceutical compositions comprising the solid forms of the selectiveandrogen receptor modulator compound, in combination with progesterone.In another embodiment, the present invention provides compositions andpharmaceutical compositions comprising the solid forms of the selectiveandrogen receptor modulator compound, in combination with estrogen. Inanother embodiment, the present invention provides compositions andpharmaceutical compositions comprising the solid forms of the selectiveandrogen receptor modulator compound, in combination with PDE5inhibitors. In another embodiment, the present invention providescompositions and pharmaceutical compositions comprising the solid formsof the selective androgen receptor modulator compound, in combinationwith apomorphine. In another embodiment, the present invention providescompositions and pharmaceutical compositions comprising the solid formsof the selective androgen receptor modulator compound, in combinationwith a bisphosphonate. In another embodiment, the present inventionprovides compositions and pharmaceutical compositions comprising thesolid forms of the selective androgen receptor modulator compound, incombination with one or more additional SARMs.

The following examples are presented in order to more fully illustratethe preferred embodiments of the invention. They should in no way beconstrued, however, as limiting the broad scope of the invention.

EXPERIMENTAL DETAILS SECTION Example 1 Synthesis of Compound S-1

(2R)-1-Methacryloylpyrrolidin-2-carboxylic Acid. D-Proline, 14.93 g,0.13 mol) was dissolved in 71 mL of 2 N NaOH and cooled in an ice bath;the resulting alkaline solution was diluted with acetone (71 mL). Anacetone solution (71 mL) of methacrylolyl chloride (13.56 g, 0.13 mol)and 2N NaOH solution (71 mL) were simultaneously added over 40 min tothe aqueous solution of D-proline in an ice bath. The pH of the mixturewas kept at 10-11° C. during the addition of the methacrylolyl chloride.After stirring (3 h, room temperature), the mixture was evaporated invacuo at a temperature at 35-45° C. to remove acetone. The resultingsolution was washed with ethyl ether and was acidified to pH 2 withconcentrated HCl. The acidic mixture was saturated with NaCl and wasextracted with EtOAc (100 mL×3). The combined extracts were dried overNa₂SO₄, filtered through Celite, and evaporated in vacuo to give thecrude product as a colorless oil. Recrystallization of the oil fromethyl ether and hexanes afforded 16.2 (68%) of the desired compound ascolorless crystals: mp 102-103° C. (lit. [214] mp 102.5-103.5° C.); theNMR spectrum of this compound demonstrated the existence of two rotamersof the title compound. ¹H NMR (300 MHz, DMSO-d₆) δ 5.28 (s) and 5.15 (s)for the first rotamer, 5.15 (s) and 5.03 (s) for the second rotamer(totally 2H for both rotamers, vinyl CH₂), 4.48-4.44 for the firstrotamer, 4.24-4.20 (m) for the second rotamer (totally 1H for bothrotamers, CH at the chiral canter), 3.57-3.38 (m, 2H, CH₂), 2.27-2.12(1H, CH), 1.97-1.72 (m, 6H, CH₂, CH, Me); ¹³C NMR (75 MHz, DMSO-d₆) δfor major rotamer 173.3, 169.1, 140.9, 116.4, 58.3, 48.7, 28.9, 24.7,19.5: for minor rotamer 174.0, 170.0, 141.6, 115.2, 60.3, 45.9, 31.0,22.3, 19.7; IR (KBr) 3437 (OH), 1737 (C═O), 1647 (CO, COOH), 1584, 1508,1459, 1369, 1348, 1178 cm⁻¹; [α]_(D) ²⁶+80.8° (c=1, MeOH); Anal. Calcd.for C₉H₁₃NO₃: C 59.00, H 7.15, N 7.65. Found: C 59.13, H 7.19, N 7.61.

(3R,8aR)-3-Bromomethyl-3-methyl-tetrahydro-pyrrolo[2,1-c][1,4]oxazine-1,4-dione.A solution of NBS (23.5 g, 0.132 mol) in 100 mL of DMF was addeddropwise to a stirred solution of the (methyl-acryloyl)-pyrrolidine(16.1 g, 88 mmol) in 70 mL of DMF under argon at room temperature, andthe resulting mixture was stirred 3 days. The solvent was removed invacuo, and a yellow solid was precipitated. The solid was suspended inwater, stirred overnight at room temperature, filtered, and dried togive 18.6 (81%) (smaller weight when dried ˜34%) of the title compoundas a yellow solid: mp 152-154° C. (lit. [214] mp 107-109° C. for theS-isomer); ¹H NMR (300 MHz, DMSO-d₆) δ 4.69 (dd, J=9.6 Hz, J=6.7 Hz, 1H,CH at the chiral center), 4.02 (d, J=11.4 Hz, 1H, CHH_(a)), 3.86 (d,J=11.4 Hz, 1H, CHH_(b)), 3.53-3.24 (m, 4H, CH₂), 2.30-2.20 (m, 1H, CH),2.04-1.72 (m, 3H, CH₂ and CH), 1.56 (s, 2H, Me); ¹³C NMR (75 MHz,DMSO-d₆) δ 167.3, 163.1, 83.9, 57.2, 45.4, 37.8, 29.0, 22.9, 21.6; IR(KBr) 3474, 1745 (C═O), 1687 (C═O), 1448, 1377, 1360, 1308, 1227, 1159,1062 cm⁻¹; [α]_(D) ²⁶+124.5° (c=1.3, chloroform); Anal. Calcd. forC₉H₁₂BrNO₃: C 41.24, H 4.61, N 5.34. Found: C 41.46, H 4.64, N 5.32.

(2R)-3-Bromo-2-hydroxy-2-methylpropanoic Acid. A mixture of bromolactone(18.5 g, 71 mmol) in 300 mL of 24% HBr was heated at reflux for 1 h. Theresulting solution was diluted with brine (200 mL), and was extractedwith ethyl acetate (100 mL×4). The combined extracts were washed withsaturated NaHCO₃ (100 mL×4). The aqueous solution was acidified withconcentrated HCl to pH=1, which, in turn, was extracted with ethylacetate (100 mL×4). The combined organic solution was dried over Na₂SO₄,filtered through Celite, and evaporated in vacuo to dryness.Recrystallization from toluene afforded 10.2 g (86%) of the desiredcompound as colorless crystals: mp 107-109° C. (lit. [214] mp 109-113°C. for the S-isomer); ¹H NMR (300 MHz, DMSO-d₆) δ 3.63 (d, J=10.1 Hz,1H, CHH_(a)), 3.52 (d, J=10.1 Hz, 1H, CHH_(b)), 1.35 (s, 3H, Me); IR(KBr) 3434 (OH), 3300-2500 (COOH), 1730 (C═O), 1449, 1421, 1380, 1292,1193, 1085 cm⁻¹; [α]_(D) ²⁶+10.50 (c=2.6, to MeOH); Anal. Calcd. forC₄H₇BrO₃: C 26.25; H, 3.86. Found: C 26.28, H 3.75.

Synthesis of(2R)-3-Bromo-N-[4-cyano-3-(trifluoromethyl)phenyl]-2-hydroxy-2-methylpropanamide.Thionyl chloride (46.02 g, 0.39 mol) was added dropwise to a cooledsolution (less than 4′C) of 6 (51.13 g, 0.28 mol) in 300 mL of THF underan argon atmosphere. The resulting mixture was stirred for 3 h under thesame condition. To this was added Et₃N (39.14 g, 0.39 mol) and stirredfor 20 min under the same condition. After 20 min,5-amino-2-cyanobenzotrifluoride (40.0 g, 0.21 mol), 400 mL of THF wereadded and then the mixture was allowed to stir overnight at roomtemperature. The solvent was removed under reduced pressure to give asolid which was treated with 300 mL of H₂O, extracted with EtOAc (2×400mL). The combined organic extracts were washed with saturated NaHCO₃solution (2×300 mL) and brine (300 mL). The organic layer was dried overMgSO₄ and concentrated under reduced pressure to give a solid which waspurified from column chromatography using CH₂Cl₂/EtOAc (80:20) to give asolid. This solid was recrystallized from CH₂Cl₂/hexane to give 55.8 g(73.9%) of(2R)-3-Bromo-N-[4-cyano-3-(trifluoromethyl)phenyl]-2-hydroxy-2-methylpropanamideas a light-yellow solid.

¹H NMR (CDCl₃/TMS) δ 1.66 (s, 3H, CH₃), 3.11 (s, 1H, OH), 3.63 (d,J=10.8 Hz, 1H, CH₂), 4.05 (d, J=10.8 Hz, 1H, CH₂), 7.85 (d, J=8.4 Hz,1H, ArH), 7.99 (dd, J=2.1, 8.4 Hz, 1H, ArH), 8.12 (d, J=2.1 Hz, 1H,ArH), 9.04 (bs, 1H, NH). Calculated Mass: 349.99, [M-H]⁻ 349.0. M.p.:124-126° C.

Synthesis of(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2-methylpropanamide.A mixture of bromoamide((2R)-3-bromo-N-[4-cyano-3-(trifluoromethyl)phenyl]-2-hydroxy-2-methylpropanamide,50 g, 0.14 mol), anhydrous K₂CO₃ (59.04 g, 0.43 mol), and 4-cyanophenol(25.44 g, 0.21 mol) in 500 mL of 2-propanol was heated to reflux for 3 hand then concentrated under reduced pressure to give a solid. Theresulting residue was treated with 500 mL of H₂O and then extracted withEtOAc (2×300 mL). The combined EtOAc extracts were washed with 10% NaOH(4×200 mL) and brine. The organic layer was dried over MgSO₄ and thenconcentrated under reduced pressure to give an oil which was treatedwith 300 mL of ethanol and an activated carbon. The reaction mixture washeated to reflux for 1 h and then the hot mixture was filtered throughCelite. The filtrate was concentrated under reduced pressure to give anoil. This oil was purified by column chromatography using CH₂Cl₂/EtOAc(80:20) to give an oil which was crystallized from CH₂Cl₂/hexane to give33.2 g (59.9%) of(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2-methylpropanamideas a colorless solid (a cotton type).

¹H NMR (CDCl₃/TMS) δ 1.63 (s, 3H, CH₃), 3.35 (s, 1H, OH), 4.07 (d,J=9.04 Hz, 1H, CH), 4.51 (d, J=9.04 Hz, 1H, CH), 6.97-6.99 (m, 2H, ArH),7.57-7.60 (m, 2H, ArH), 7.81 (d, J=8.55 Hz, 1H, ArH), 7.97 (dd, J=1.95,8.55 Hz, 1H, ArH), 8.12 (d, J=1.95 Hz, 1H, ArH), 9.13 (bs, 1H, NH).Calculated Mass: 389.10, [M-H]^(˜)388.1. Mp: 92-94° C.

Example 2 Crystallization of S-1 SARM Compound

Materials and Methods

Methods:

X-Ray Powder Diffraction (XRPD)

XRPD was used for the determination of the crystal structure orrecognition of liquid crystals materials in partially crystallinemixtures. XRPD was performed with PANalytical X-ray diffractometer PW1710, where the tube anode was Cu with Ka radiation. The pattern wascollected in step scan mode (step size of 0.02 °2θ, counting time 2.4s/step. The sample was measured without any special treatment other thanthe application of slight pressure to get a flat surface. Themeasurements were performed at an ambient air atmosphere.

Raman Spectroscopy

FT-Raman spectra were recorded on a Bruker RFS 100 FT-Raman system witha near infrared Nd:YAG laser operating at 1064 nm and a liquidnitrogen-cooled germanium detector. For each sample, 64 scans with aresolution of 2 cm⁻¹ were accumulated. The laser power used was at 100mW. Raman measurements were conducted using aluminum sample holders orhermetically closed glass tubes at room temperature.

Thermo Gravimetric-Fourier Transform Infrared (TG-FTIR) and ThermoGravimetric Analysis

The TG-FTIR instrument consists of a thermogravimetric analyzer (TG)coupled with a Fourier-Transform Infrared (FTIR) spectrometer for theanalysis of evolved gases such as gases of H₂O, by their mass losscombined with characterization of the evolved components. Thermogravimetric measurements were carried out with a NetzschThermo-Microbalance TG 209 coupled to a Bruker FTIR Spectrometer Vector22. Sample pans with a pinhole were used under an N₂ atmosphere, at aheating rate of 10 K/min, with a temperature range of 25 to 250° C.Additional Thermo Gravimetric Analysis was conducted using a TAInstruments Q500 TGA under various conditions.

Differential Scanning Calorimetry (DSC)

Thermal analysis was carried out with a Perkin Elmer DSC7 with thefollowing experimental conditions: 3 to 6 mg sample mass, closed goldsample pan, temperature range −50° C. to 120° C., heating rate 20 K/minThe samples were weighed in air or dry N₂ atmosphere. Additional thermalanalysis was conducted using a TA Instruments Q1000 DSC using hermeticaluminum pans under various conditions.

Dynamic Vapor Sorption (DVS)

Dynamic vapor sorption quantification relates the mass of water absorbedand subsequently desorbed during the crystallization process. In orderto define whether batch P1, P2 and P4 are hydrated polymorphs, DVSmeasurements were conducted (FIG. 9). A sample (13 to 14 mg) was placedon a Pt pan, and the sample was allowed to equilibrate at 25° C./50%r.h. before starting a pre-defined humidity program (1.0 hours 50%, from50% r.h. to 95% r.h.: 5% r.h./hour, 10 hours at 95% r.h., from 95% r.h.to 0% r.h.: 5% r.h./hour, 10 hours at 0% r.h., from 0 r.h. to 50% r.h.:5% r.h./hour, 1 hours at 50% r.h.

Scanning Electron Spectroscopy (SEM)

Images of S-1 batch P1, P2 and P4 (FIG. 8) were taken with an SEMCamScan CS24 system.

Filtration

During the following experiments: suspension equilibration,precipitation experiment, recrystallization, relative stabilityexperiments and water solubility experiment, a filtration step wasconducted. Centrifugal filter devices: Ultrafree-CL (0.22 la,m),Millipore; Centrifuge type or Eppendorf 5804R were used at a temperatureof 22° C. and centrifugation program of 2 min 3000 rpm.

High Performance Liquid Chromatography (HPLC)

HPLC was used to analyse the purity of S-1. HP 1090M HPLC machine wasused with the following conditions:

-   Column: Symmetry Shield RP18, 3.9×150 mm, 5 μm-   Column temperature: 35° C.-   Injection volume: 10 μL-   Solvent: acetonitrile+water 1:1 v/v-   Mobile phase A: 0.1% TFA—water-   Mobile phase B: 0.1% TFA—acetonitrile-   Flow rate: 1 mL/min-   Detection: UV at 271 nm-   Run time: 21 min-   Retention time (S-1): 10.7 min    Materials:    Solvents

For all experiments, Fluka or Merck grade solvents were used. Water:deionized (Fluka No. 95305)

Chemicals

Compound S-1 was synthesized as described in Example 1.

Results:

Four batches of S-1 compound designated accordingly, (S-1-P1), (S-1-P2),(S-1-P3), and (S-1-P4) were selected for characterization. S-1-P1,S-1-P2, and S-1-P3 were individual batches prepared by the syntheticprocess described in Example 1. Batch S-1-P4 was a sample of batchS-1-P1 exposed to 40 C/75% r.h. during storage. The followingexperiments were conducted to determine the stability, solubility andcharacteristics of different solid forms of S-1 compound.

The following table presents the X-ray diffraction results of form A ofS-1 as depicted in FIG. 4A:

Angle d value Intensity Intensity 2-Theta ° Angstrom Cps % % 5.56 15.92250 30 7.47 11.8 470 6 8.61 10.3 1399 19 9.93 8.9 3016 40 12.41 7.1 7079 14.94 5.93 2647 35 16.66 5.32 6922 92 17.31 5.12 1049 14 18.03 4.92397 5 18.52 4.79 930 12 19.25 4.61 830 11 19.83 4.47 823 11 20.63 4.30740 10 21.80 4.07 988 13 22.33 3.98 7557 100 23.45 3.79 976 13 23.923.72 914 12 24.56 3.62 376 5 24.92 3.57 589 8 25.39 3.51 774 10 25.953.43 618 8 26.50 3.36 353 5 27.79 3.21 2123 28 28.80 3.10 734 10 29.683.01 410 5 30.07 2.97 656 9 30.49 2.93 423 6 31.42 2.84 391 5 32.49 2.75330 4 33.66 2.66 431 6 34.78 2.58 444 6

The following table presents the X-ray diffraction results of form A+Cof S-1 as depicted in FIG. 12D, wherein the diffraction angles of form Cwere identified:

Mixture Form A with Form C Peak Assignment Angle d value IntensityIntensity not form A line 2-Theta ° Angstrom Cps % 5.65 15.6 100 41certain 6.89 12.8 7 3 7.43 11.9 8 3 8.68 10.2 42 17 probable 9.46 9.3 2510 9.94 8.9 111 45 11.20 7.9 7 3 12.60 7.0 12 5 certain 13.49 6.6 9 414.89 5.95 82 33 15.17 5.84 22 9 Probable 15.99 5.54 41 17 16.84 5.26164 67 17.21 5.15 64 26 18.00 4.92 17 7 18.54 4.78 45 18 19.37 4.58 2711 19.86 4.47 39 16 20.66 4.29 21 9 21.79 4.08 46 19 22.36 3.97 246 100certain 22.84 3.89 52 21 23.53 3.78 46 19 23.91 3.72 38 15 24.84 3.58 167 25.41 3.50 37 15 26.15 3.41 14 6 26.60 3.35 12 5 27.89 3.20 60 2428.86 3.09 31 13 30.01 2.98 30 12 30.52 2.93 14 6 30.98 2.88 13 5 31.342.85 15 6 32.72 2.73 14 6 33.93 2.64 15 6 34.84 2.57 15 6

In one embodiment form C has additional lines which are overlaid bysignals of form A.

Peak search and d-value calculation were performed with software EVAversion 10, 0, 0, 0, Cu Kalpha2 was removed by software, and only linesup to 35° 2theta were listed.

The sample PP148-P1 was measured on a 0.1 mm sample holder on aPANalytical PW1710 diffractometer.

The sample PP148-P52 was measured on a 0.1 mm sample holder on a BrukerD8 Advance diffractometer.

The following table presents the X-ray diffraction results of form D ofS-1 as depicted in FIG. 18 (bottom):

Angle d value Intensity 2-Theta ° Angstrom Cps I/Imax 4.42 19.99 17733100.0 8.48 10.41 3026 17.1 8.80 10.04 1755 9.9 11.35 7.79 4598 25.911.76 7.52 805 4.5 12.72 6.96 1462 8.2 13.84 6.39 8635 48.7 14.45 6.135597 31.6 14.64 6.05 9445 53.3 15.10 5.86 7013 39.5 16.14 5.49 1644 9.316.64 5.32 1678 9.5 16.95 5.23 2357 13.3 17.41 5.09 484 2.7 17.59 5.04678 3.8 18.04 4.91 2308 13.0 18.71 4.74 3439 19.4 19.04 4.66 1824 10.319.46 4.56 4093 23.1 20.48 4.33 989 5.6 20.84 4.26 7616 42.9 22.15 4.015058 28.5 22.78 3.90 1933 10.9 23.15 3.84 3851 21.7 23.47 3.79 2352 13.323.88 3.72 5583 31.5 24.74 3.60 10043 56.6 24.94 3.57 5395 30.4 25.293.52 3149 17.8 25.67 3.47 1290 7.3 26.14 3.41 692 3.9 26.46 3.37 10956.2 27.80 3.21 2402 13.5 28.32 3.15 1565 8.8 28.64 3.11 998 5.6 28.903.09 1212 6.8 29.38 3.04 3295 18.6 29.92 2.98 756 4.3 30.40 2.94 12787.2 31.19 2.87 851 4.8 31.86 2.81 1270 7.2 32.49 2.75 775 4.4 32.82 2.73920 5.2 33.66 2.66 842 4.7 34.50 2.60 977 5.5 35.80 2.51 638 3.6 36.062.49 700 3.9 36.83 2.44 777 4.4 37.16 2.42 698 3.9 38.02 2.36 733 4.138.44 2.34 859 4.8 38.97 2.31 844 4.8 39.99 2.52 791 4.5 40.89 2.21 6413.6 41.30 2.18 515 2.9Water Vapor Sorption (Humidity Chamber)

The compound was stored in a glass tube under 96% r.h. (relativehumidity) in a humidity chamber at room temperature. After differenttime of storage Raman measurements were conducted using hermeticallyclosed glass tubes. The results are summarized in Table 1:

TABLE 1 Start- Concen- ing tration Form form Solvent mg/ml Conditionsproduced A stored in humidified (powder) chamber 96% r.h./23° C.  4weeks A + small amount form B′  9 weeks A + form B′ 11 weeks A + approx.20% form B′ (see FIG. 17A) A water 111/5.0 23° C. (suspension)sonication 5 min. (suspension) stirred 19 h/37° C. B′ filtered & airdried (see FIG. 17B) A water + 5% 123/2.1 23° C. (suspension) ethanolstirred 3 h/83° C. viscous sticky v/v mass cooled to 47° C. within B′1.5 h filtered & air dried A acetic 138/2.0 23° C. (suspension)acid/water stirred 20 h/23° C. A 1:2 v/v filtered & air dried (see FIG.17C) A water + 5% 105/2.0 23° C. (suspension) acetic stirred 12 min/40°C. (suspension) acid v/v sonicated 2 min. (suspension) stirred 17 h/40°C. viscous sticky cooled to R.T. and mass B′ removed solutionMeasurement of the Approximate Solubility

To determine the approximate solubility at room temperature, the solventwas added in steps to the solid material. After every addition, thesample was well stirred. The addition of solvent was continued untilcomplete dissolution or until 15 ml of solvent was added. The solubilityof solid form A and B′ at 23° C. is presented in Table 2.

TABLE 2 Solid Solubility Solvent form (mg/ml) ethanol A >200 acetoneA >200 TBME A >200 ethyl acetate A >200 THF A >200 acetonitrile A >200dichloromethane A >200 1,4-dioxane A >200 acetic acid A >200 toluene A<6 turbid solution ethanol/water A >200 3:1 v/v ethanol/water A 50 1:1v/v ethanol/water A <5 1:3 v/v ethanol/n-heptane A 180 1:1 v/vethanol/n-heptane A 50 1:3 v/v acetone/n-heptane A >200 1:1 v/vacetone/n-heptane A 90 1:3 v/v THF/n-heptane A >200 1:1 v/vTHF/n-heptane A 65 1:3 v/v acetonitrile/ A >200 toluene 1:1 v/vacetonitrile/ A 170 toluene 1:3 v/v ethyl acetate/ A 65 n-heptane 1:1v/v ethyl acetate/ A 9 n-heptane 1:2 v/v ethyl acetate/ B′ >9 solid formn-heptane transformation into 1:2 v/v solid form A ethyl acetate/ A 13n-pentane 1:2 v/v ethyl formate/ A 12 n-pentane 1:2 v/v methyl acetate/A 8 n-pentane 1:2 v/v ethyl acetate/ A <5 turbid solution n-heptane 1:3v/vSuspension Equilibration Experiments

Suspension equilibration experiments were carried out with 81-128 mg ofthe compound. The suspensions were stirred with a magnetic stirrer. Thesamples obtained after filtration were air dried at ambient temperaturefor a short time only to prevent possible desolvation of labile hydratesor solvates. The results of the suspension equilibration experiments ofsolid form A and B′ are presented in Table 3.

TABLE 3 Start- Concen- ing tration Form form Solvent mg/ml Conditionsproduced A n-heptane 108/2.0 23° C. (suspension) sonicated 5 min.(suspension) stirred 17 A h/37° C. (see FIG. 10a) filtered & air dried An-heptane + 5% 117/2.1 23° C. (suspension) ethanol v/v sonicated 5 min.(suspension) stirred 18 A h/37° C. filtered & air dried B′ ethylacetate + n-  81/1.7 23° C. (suspension) heptane 1:2 v/v stirred 2 Ah/23° C. (see FIG. 10b) filtered & air dried A ethyl acetate + n-124/2.0 23° C. (suspension) heptane 1:2 v/v stirred 3 A days/23° C.filtered & air dried A ethyl acetate + n- 126/2.0 +2° C. (suspension)heptane 1:2 v/v stirred 3 A days/+2° C. filtered & air dried B′ ethylacetate + n- 101/1.0 23° C. (suspension) pentane 1:2 v/v stirred 22 Ah/23° C. (see FIG. 13c) filtered & air dried A ethyl acetate + n-128/2.0 23° C. (suspension) pentane 1:2 v/v stirred 20 A h/23° C. (seeFIG. 10d) filtered & air dried A ethyl formate + n- 112/2.0 23° C.(suspension) pentane 1:2 v/v stirred 20 A h/23° C. (see FIG. 10e)filtered & air dried A methyl acetate + n- 126/2.0 23° C. (suspension)pentane 1:2 v/v stirred 20 A h/23° C. (see FIG. 10f) filtered & airdriedVapor Diffusion Experiments

Vapor diffusion experiments were carried out with solution of thecompound in different solvents. The solutions were placed in small, opencontainers that were stored in larger vessels containing miscible,volatile antisolvents. The larger vessels were then tightly closed. Theantisolvents diffused through the vapor phases into the solutions, andsaturation or supersaturation was achieved. The results of the vapordiffusion experiments of solid form A and B′ are presented in Table 4.

TABLE 4 Concen- Anti- tration Form Solvent solvent mg/ml Conditionsproduced ethanol n-hexane 204 mg P1 vapor diffusion, viscous sticky 0.4ml 23° C., mass solvent 7 days, removed solution acetone n-hexane 210 mgP1 vapor diffusion, viscous sticky 0.5 ml 23° C., mass solvent 7 days,removed solution TBME n-hexane 205 mg P1 vapor diffusion, viscous sticky0.6 ml 23° C., mass solvent 7 day, removed solution ethyl acetaten-hexane 206 mg P1 vapor diffusion, very similar 0.6 ml 23° C., 2 days,to A solvent filtered and air-dried THF n-hexane 212 mg P1 vapordiffusion, viscous sticky 0.6 ml 23° C., mass solvent 7 days, removedsolution toluene n-hexane 44 mg P1 vapor diffusion, very similar 2.0 ml23° C., to A solvent 2 days, removed (see FIG. 11A) solution dichloro-n-hexane 204 mg P1 vapor diffusion, very similar methane 1.6 ml 23° C.,to A solvent 2 days, removed solution 1,4-dioxane n-hexane 215 mg P1vapor diffusion, viscous sticky 0.5 ml 23° C., mass solvent 7 days,removed solution acetic acid water 219 mg P1 vapor diffusion, verysimilar 0.3 ml 23° C., to A solvent 7 days, removed (see FIG. 11B)solution acetonitrile water 212 mg P1 vapor diffusion, viscous sticky0.4 ml 23° C., mass solvent 6 days, removed solutionEvaporation Experiments

Solutions of the compound were dried at room temperature (dry nitrogenflow) without stirring. The results of the evaporation experiments ofsolid form A are presented in Table 5.

TABLE 5 Start- Concen- ing tration Form form Solvent mg/ml Conditionsproduced A ethanol 100/2.0 23° C. (solution) evaporated(dry N2) 2 B″days/23° C. A ethyl 109/2.0 23° C. (solution) acetate evaporated (dryN₂) 1 very similar day/23° C. to A (see FIG. 12A) A THF 183/2.0 23° C.(solution) evaporated (dry N₂) 5 A + C days/23° C. (see FIG. 12B)Precipitation Experiments

Precipitation experiments were carried out with 42-79 mg of thecompound. The to non-solvent was added to the solution. The samplesobtained after filtration (glass filter porosity P4) were air dried atambient temperature and for a short time only to prevent possibledesolvation of labile hydrates or solvates. The results of theprecipitation experiments of solid form A are presented in Table 6.

TABLE 6 Start- Concen- ing tration Form form Solvent mg/ml Conditionsproduced A ethanol 79/0.2 23° C. (solution) 79/1.2 added of 1.0 ml n-(phase heptane separation) stored 11 weeks/−20° C.; very similar removedsolution to A and dried solid residue (N₂ 43 ml/min) 50 min R.T. A ethyl42/0.2 23° C. (solution) acetate 42/1.2 added of 1.0 ml n- (viscoussticky heptane mass) stirred 14 h/40° C. A filtered & air dried A THF62/0.2 23° C. (solution) 62/1.2 added of 1.0 ml n- (viscous stickyheptane mass) stirred 14 h/40° C. A filtered & air dried A dichloro-75/0.3 23° C. (solution) methane 75/1.2 added of 1.0 ml n- (viscoussticky heptane mass) stirred totally 13 h/ A 40° C. filtered & air driedRecrystallization from Solution

The compound was dissolved in different solvent systems at roomtemperature and cooled to +5° C. or to −20° C. The samples obtainedafter filtration (glass filter porosity P4) were air dried at ambienttemperature for a short time only to prevent possible desolvation oflabile hydrates or solvates.

The results of the recrystallization experiments of solid form A arepresented in Table 7.

TABLE 7 Start- Concen- ing tration Form form Solvent mg/ml Conditionsproduced A ethanol + 72/0.4 23° C. (solution) n-heptane stored 4weeks/+5° C.; A 1:1 v/v filtration, washed (n- heptane) and air-dried Aethyl 80/1.2 23° C. (solution) acetate + stored 4 weeks/−20° C.; verysimilar n-heptane filtered and air-dried to A 1:1 v/v (see FIG. 13A) Aacetonitrile + 91/0.2 23° C. (solution) toluene stored 4 weeks/−20° C.;very similar 1:1 v/v removed solution and to A dried solid residue (N₂43 ml/min) 212 min R.T. A ethanol+ 52/0.4 23° C. (solution) n-heptanestored 1 day/+5° C.; A 1:3 v/v filtered, washd (n- heptane) andair-dried A acetonitrile + 65/0.4 23° C. (solution) toluene stored 4weeks/−20° C.; very similar 1:3 v/v filtered and air-dried to A (seeFIG. 16B)Freeze Drying Experiment

The compound was dissolved in 1,4-dioxane and the solution was cooled to−50° C. During sublimation of the solvent the temperature of the solidwas <0° C. as presented in Table 8:

TABLE 8 Start- Concen- ing tration Form form Solvent mg/ml Conditionsproduced A 1,4-dioxane 102/2.0 23° C. (solution) PP148-P1 freeze dried<0° C. viscous sticky mass stored 12 days/R.T. very similar to A (seeFIG. 14)Drying Experiment

The sample was dried overnight in a dry N₂-atmosphere at roomtemperature before closing the DSC sample pan.

The results are summarized in Table 9:

TABLE 9 Starting form mg Conditions DSC B′ 3.6 mg dried overnight 23° C.FIG. 15 (mass loss 1.0%)Cooling and Reheating of the Melt Experiments

After heating in DSC to 120° C. the samples were cooled to −50° C. andreheated to 120° C. The results are summarized in Table 10:

TABLE 10 Starting form mg Conditions DSC A 3.4 mg fast cooled to −50°C., FIG. 7A heated: −50° C. to 120° C./20 K/min, fast cooled to −50° C.heated again: −50° C. to 120° C./20 K/min A 4.4 mg fast cooled to −50°C. FIG. 7B PP148-P2 heated: −50° C. to 120° C./20 K/min fast cooled toto −50° C. C. heated again: −50° C. to 120° C./20 K/min A 3.4 mg fastcooled to −50° C. FIG. 7C heated: −50° C. to 120° C./20 K/min fastcooled to −50° C. C. heated again: −50° C. to 120° C./20 K/min B′ 2.9 mgfast cooled to −50° C. FIG. 7D heated: −50° C. to 120° C./20 K/min fastcooled to −50° C. heated again: −50° C. to 120° C./20 K/minRelative Stability Experiments

Suspension experiments were carried out with 130-145 mg of the compound.The suspensions were stirred with a magnetic stirrer and filtered aftera predefined time. The samples obtained after filtration (glass filterporosity P4) were air dried at ambient temperature. The results aresummarized in Table 11:

TABLE 11 Start- Concen- ing tration Form forms Solvent mg/ml Conditionsproduced A ethyl approx. 23° C. (suspension) acetate/n- 130/2.0 stirred3 days/ A heptane 23° C.; (see FIG. 16A) 1:2 (v/v) filtered andair-dried A ethyl (81 + 64)/2.0 23° C. (suspension) acetate/n- stirred 1day/ A heptane 23° C.; (see FIG. 16B) 1:2 (v/v) filtered and air-driedWater Solubility of Solid Forms A and B′

Suspensions of the solid forms (25 or 50 mg in 3.5 or 7.0 ml bidistilledwater) were shaken (800 rpm) and filtered after 0.5 h, 1.5 h, 4 h and 20h. After filtration the solid residue was checked by Raman spectroscopyand the concentration in the clear solution was determined by HPLC.

The solubility of solid form A of S-1 in water at 22° C. is summarizedin Table 12:

TABLE 12 Suspension equilibration Solubility^(a)) time [h] [mg/1000 ml]Solid residue^(b)) 0.5 21.0 ± 3.9 A + B′ (approx. 95% + 5%)^(c)) 1.524.0 ± 1.4 A + B′ (approx. 90% + 10%)^(c)) 4.0 27.6 ± 1.5 A + B′(approx. 85% + 15%)^(c)) 20   24.5 ± 1.7^(d)) A + B′ (approx. 75% +25%)^(c)) ^(a))Mean value of two measurements (±standard deviation)^(b))Raman measurements ^(c))Rough estimate ^(d))pH of the solution: 8.7

The solubility of Form B′ of S-1 in water at 22° C. is summarized inTable 13:

TABLE 13 Suspension equilibration Solubility ^(a)) time [h] [mg/1000 ml]Solid residue ^(b)) 0.5 27.4 ± 0.9 B′ 1.5 27.3 ± 0.8 B′ 4.0 25.6 ± 0.1B′ 20  26.7 ± 0.3 ^(c)) B′ ^(a)) Mean value of two measurements(±standard deviation) ^(b)) Raman measurements ^(c)) Rough estimate^(d)) pH of the solution: 8.7Characterization of S-1-P1 Form A

The starting material for the polymorphism study, batch no. S-1-P1, iscrystalline and the crystal form A. TG-FTIR shows that the mass loss upto 200° C. is very low (<0.2%) and therefore batch no. S-1-P1 is not ahydrate or solvate. Batch no. S-1-P1 melts at 82° C. (DSC peaktemperature, heating rate 20K/min) After melting and fast cooling to−50° C. in DSC the anhydrous liquid crystal form was produced. Thesample showed a phase transition temperature of approx. 52° C. and didnot recrystallize during heating in DSC. S-1-P1 might contain a smallamount (roughly estimated 5%) of form B′ or B″.

The DVS measurement of form A at 25° C. does not show any evidence ofclassical hydrate formation under the experimental conditions used. Themaximum water content at 93% relative humidity. is 1.5%. The very slighthysteresis is most probably caused by a viscous layer (possiblyconsisting of solid form B′) on the surface of the particles, whichinfluences the rate of water exchange. In fact, after storing form A at96% relative humidity at room temperature for 11 weeks, Ramanspectroscopy and DSC indicated the formation of approx. 20% of form B′.

Characterization of Solid Form B′

Investigations by DSC and XRPD indicate that the solid form producedduring storage of solid form A at 40° C. and 75% relative humidity.(batch S-1-P4; 40° C./75% RH) is a paracrystalline form, having limitedlow-range order. This limited order most probably is responsible for theendothermal peak in DSC around 55° C. and the broad shoulder around 17°in the diffraction pattern. The solid form of batch S-1-P4 40° C./75%relative humidity is Form B′.

The DVS behavior of solid form B′ at 25° C. is not the typical sorptionbehavior of a hydrate. The maximum water content at 94% relativehumidity. is approx. 2.4%. Even though a certain hysteresis is observed,there is no clear step in the sorption curve which would clearlyindicate the existence of a classical hydrate.

Formation of Solid Form B′

In addition to the observed transformation at high relative humidity,solid form B′ can be produced by stiffing a suspension of solid form Ain water at 37° C. overnight.

Formation of Solid form B″

Pathways to produce solid form B″ are melting and cooling of the melt,and slow evaporation of solutions in solvents such as ethanol. PolymorphB″ can be prepared from polymorphs A and D by heating them to abovetheir respective melting points of 80° C. and 130° C. B′ and B″ are notdistinguishable from any analytical methods used thus far but aredistinguished based on their routes of formation. B′ is assigned as alyotropic liquid crystalline form due to its solvent mediated formationwhile B″ is assigned as a thermotropic liquid crystalline form from itsthermal method of preparation. Evaporation of the drug from solventssuch as ethanol without an antisolvent also produces B″.

Formation of Solid Form C

Polymorph C can only be obtained as a mixture with A by dissolving andsubsequently evaporating the drug out of THF at ambient temperature.

Formation of Solid Form D

Polymorph D was originally produced by crystallization from asolvent/antisolvent mixture at 50° C. using ethyl acetate andcyclohexane as the solvent and antisolvents respectively. Form D canalso be prepared from other polymorphic forms by “seeding” the samplewith a small amount of D and storing it at 110° C./0% RH for 7 days orat 50° C. in water for 24 hours and drying.

Formation of Solid Form Toluene Solvate

The toluene solvate was prepared by any solvent/antisolventcrystallization method that used toluene as the antisolvent.

Water Solubility of Solid Forms A and B′

The solubility of forms A and B′ of compound S-1 in water at 22° C. are24.0±1.4 mg/1000 ml and 27.3±0.8 mg/1000 ml, values obtained after 1.5 hsuspension equilibration time. These solubilities are very similarbecause of the fast transformation of form A into form B′ on the surfaceof the particles during the solubility experiments.

Characterization of Different Batches of Solid Form A

Samples of batches S-1-P1, S-1-P2 and S-1-P3 show the same diffractionpattern. to DSC measurements show that they most probably containseveral % of solid form B′ or B″, indicated by heat capacity changesaround 50° C. Sample S-1-P2 shows the highest level of solid form B′ orB″ (approx 20%). To better understand the DSC results, scanning electronmicrographs (SEM) of samples S-1-P1 and S-1-P2 were produced. Whereasthe pictures of sample S-1-P1 show quite well-formed particles, thepictures of sample S-1-P2 show a partial transformation, possibly causedby too high a drying temperature or partial contact with water. Thepartial formation of solid form B′ or B″ could also be caused by fastprecipitation and a relatively high antisolvent/solvent ratio afterprecipitation. Other explanations would be drying at high temperaturesor storage under high humidity conditions.

Solvent Systems for Crystallization of Solid Form A

Crystal form A is highly soluble in a number of solvents commonly usedfor crystallization. Due to its high solubility, solvent/antisolventmixtures are necessary for crystallization.

Suspension equilibration experiments at room temperature revealed thatsolid form B′ (batch S-1-P4; 40° C./75% RH) can be transformed intosolid form A when stirring suspensions in ethylacetate/heptane 1:2 v/vor ethylacetate/pentane 1:2. In addition, suspension equilibrationexperiments using solid form A in ethyl formate/pentane 1:2 v/v andmethyl acetate/pentane 1:2 v/v showed no transformation of solid form A.Therefore, these class 3 solvent/antisolvent mixtures can be used forcrystallization of form A. The advantages of these solvent systems arethe significantly lower boiling temperatures and therefore the possiblylower drying temperatures.

The details of the characterization of S-1-P1, solid Form A are given inTable 14:

TABLE 14 Compound S-1 Batch no. S-1-P1 XRPD solid form A FIGS. XRPD-1aand XRPD-1b (see FIG. 4A) Raman solid form A FIG. Raman-1 (see samplemight contain a small FIG. 5A) amount of B′ or B″ TG-FTIR mass loss 25°C. to 245° FIG. TG-FTIR-1 C.: <0.2% (see FIG. 6A) DSC meltingtemperature: 82.4° C. FIGS. DSC-1a and (peak temperature, hermeticallyDSC-1b (See FIG. sealed gold sample pan, 7A) heating rate 20 K/min) AH:−42 J/g sample might contain a small amount (roughly estimated 5%) ofform B′ or B″ SEM quite well-formed particles FIGS. SEM-1 (see FIG. 8ADVS water content at 50% r.h.: 0.4% FIGS. DVS-1a and maximum watercontent at 93% DVS-1b (FIG. 9A r.h.: 1.5%

The details of the characterization of S-1-P2, solid Form A, are givenin Table 15:

TABLE 15 Compound S-1 Batch no. S-1-P2 XRPD solid form A FIGS. XRPD-2aand XRPD-2b (see FIG. 4B) Raman solid form A + B′ or B″ FIG. Raman-2(See FIG. 5B) TG-FTIR mass loss 25° C. to 245° FIG. TG-FTIR-2 C.: <0.2%(see FIG. 6B) DSC melting temperature: 85.4° C. FIGS. DSC-2a and (peaktemperature, hermetically DSC-2b (see FIG. sealed gold sample pan, 7B)heating rate 20 K/min) AH: −43 J/g sample contains approx. 20% of formB′ or B″ SEM pictures show partial FIGS. SEM-2 (see transformation FIG.8B) DVS water content at 50% r.h.: 0.3% FIGS. DVS-2a and maximum watercontent at 95% DVS-2b (see FIG. r.h.: 0.6% 9B)

The details of the characterization of S-1-P3, solid Form A, are givenin Table 16:

TABLE 16 Compound S-1 Batch no. S-1-P3 XRPD solid form A FIGS. XRPD-3aand XRPD-3b (see FIG. 4C) Raman solid form A FIG. Raman-3 (see samplemight contain a small FIG. 5C) amount of B′ or B″ TG-FTIR mass loss 25°C. to 245° FIG. TG-FTIR-3 C.: <0.2% (see FIG. 6C DSC meltingtemperature: 84.4° C. FIGS. DSC-3a and (peak temperature, hermeticallyDSC-3b (see FIG. sealed gold sample pan, 7C heating rate 20 K/min) AH:−42 J/g sample might contain a small amount (roughly estimated 5%) ofform B′ or B″ SEM not analyzed — DVS not analyzed —

The details of the characterization of S-1-P4, solid Form B′ are givenin Table 17:

TABLE 17 Compound S-1 Batch no. S-1-P4 40° C./75% RH XRPD solid form B′FIGS. XRPD-4a sample might contain a small and XRPD-4b (see amount ofform A FIG. 4D) Raman solid form B′ FIG. Raman-4 (see FIG. 5D) TG-FTIRmass loss 25° C. to 245° FIG. TG-FTIR-4 C.: 1.0% (water) (see FIG. 6D)DSC endothermal peak: ~55° C. FIGS. DSC-4a and (peak temperature,hermetically DSC-4b (see FIG. sealed gold sample pan, heating 7D) rate20 K/min) AH: ~10 J/g SEM significant change in morphology FIGS. SEM-3(see FIG. 8C) DVS water content at 50% r.h.: ~0.8% FIGS. DVS-3a andmaximum water content at 94% DVS-3b (see FIG. r.h.: ~2.4% 9C)

The different batches P1, P2 and P3 of compound S-1 revealed crystallineForm A with similar characteristic behavior of XRPD, Raman, TG FTIR, DVSand DSC results. Batch P4 revealed a paracrystalline solid form ascharacterized by its broad XRPD, Raman, TG FTIR, DVS and DSC results asdescribed hereinabove.

Relative Stability of Polymorphic Forms Under Dry Conditions

The DSC thermogram of A and D in FIG. 19 show that A melts near 80° C.while D has a melting point near 130° C. The enthalpy of melting for Ais 40±5 J/g while the enthalpy of melting is 75±5 J/g. The meltingtemperature and enthalpy suggest that D possesses greater stability incomparison to form A.

FIG. 17D shows that melting of polymorphs A or D produces the liquidcrystalline B″ polymorph instead of a truly isotropic liquid phase.Formation of a true liquid phase was not observed even after heating thesample to 200° C. Cooling the B″ polymorph to ambient temperature doesnot result in recrystallization back to form A or D. This is verified bythe absence of a melting endotherm in the DSC curve (FIG. 17D) of thesample reheated after it was melted then subsequently cooled to ambienttemperature. The DSC curve also shows that the B″ form undergoes a phasetransition near 55° C. Similar glass transitions are observed for B′,which along with the broad shoulder around 17° in FIG. 4D are the basisfor their designation as liquid crystalline phases. The XRPD displaysharmonic peaks for B′, along with the broad shoulder around 17° in FIG.4D which are the basis for their designation as liquid crystallinephases.

FIG. 17 e shows that heating of polymorphs A and B″ to 110° C. in thepresence of D causes the A and B″ forms to rearrange into D. Thisconfirms that the A and B″ are metastable phases below 130° C. that canbe converted to form D. However, likely due to the high energeticbarrier for the transition, the rates of conversion of A or B″ to D arevery slow without any D present initially to seed the crystallization.Thus forms A and B″ can be considered to be practically stable atambient temperature. Above 130° C., form D melts and changes to B″ whichnow becomes the most stable form. Micronization of the polymorph Aparticles under dry conditions also produced—25% conversion to B″.

Relative Stability of Polymorphic Forms Under Humid Conditions

Polymorph A stays stable in its A form for at least 7 days under storageconditions of ambient temperature/75% RH (Relative Humidity), ambienttemperature/100% RH, 30° C./75% RH and 50° C./0% RH. But it converts toB′ when stored at 50° C./75% RH. Some of the results are shown in FIG.17F. In fact, polymorph A stored at 25° C./60% RH and 30° C./65% RH werestable through 36 months and 9 months respectively while a sample storedat 40° C./75% RH converted to B′ within one month. These resultsindicate that polymorph A converts to B′ in the presence of moisture.

Polymorph D on the other hand, remains stable at 50° C./75% RH as wellas the other conditions of ambient/75% RH, ambient/100% RH, 30° C./75%RH and 50° C./0% RH. In fact, polymorph D in the presence of moistureacts as the seed for the crystallization process and drives thetransformation of polymorphs A and B′ into D, similar to its role inseeding the A to D crystallization in dry conditions. FIG. 17G(a) showsthe time evolution of polymorph A seeded with a small amount of D at 50°C./75% RH. The amount of polymorph D initially added to the sample isvery small that it isn't detectable by the DSC with heating rate of 10°C./min. After 24 hours, most of the polymorph form A has been convertedto B′ but a small amount of sample has also been converted to D and theamount of sample in D increases over time. The transformation process isspeeded up in FIG. 17G(b) by storing the sample in water at 50° C. FormA has been converted to both B′ and D after 6 hours but the sample ispredominantly in form D by 24 hours. This is in contrast to theconversion to B′ of the pure A form which doesn't convert further to D.It is yet unclear if A can convert to D directly with seeding in wateror if it only converts to B′ (which subsequently converts to D inwater). Further work has shown that the A and B′ convert to D in thepresence of moisture at lower temperatures also albeit at slower rates.

Relative Stability of Toluene Solvate in Toluene

Recrystallization of S-1 from a solvent/antisolvent system that usestoluene as the antisolvent produces the toluene solvate. Toluene solvatehas a melting point near 100° C. with the enthalpy of melting 70±5 J/g.TGA graph of the toluene solvate in FIG. 20 shows that the toluenecontent in the solvate is ˜7% which corresponds to one toluene moleculefor every three molecules of S-1. The solvent/drug mass ratio stayed thesame for each sample batch prepared and suggests that the toluenemolecules reside inside the unit cell structure rather than in channelsor layers outside the lattice. Owing to the low solubility of S-1 intoluene (<2 mg/mL), no noticeable transformation from form D to thetoluene solvate was observed after suspension (50 mg/mL) in toluene for4 days both at ambient temperature and 50° C. Sonication of thesuspension for 10 minutes did produce partial transformation to thetoluene solvate.

It will be appreciated by a person skilled in the art that the presentinvention is not limited by what has been particularly shown anddescribed hereinabove. Rather, the scope of the invention is defined bythe claims that follow:

What is claimed is:
 1. A paracrystalline form of(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2-methylpropanamidecompound whereby said paracrystalline form is paracrystalline form B″characterized by: a. an X-ray powder diffraction pattern produced usinga tube anode of Cu with Ka radiation, said diffraction patterndisplaying a broad halo with two harmonic peaks between 15-25°2θ and b.a phase transition point of about 55° C. as determined by differentialscanning calorimetry (DSC).
 2. A composition comprising theparacrystalline form B″ of(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2-methylpropanamideof claim 1 and a suitable carrier or diluent.
 3. A process for thepreparation of a paracrystalline form B″ of compound(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2-methylpropanamideaccording to claim 1 comprising evaporation of said compound fromethanol without an antisolvent.
 4. A process for the preparation of aparacrystalline form B″ of compound(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2-methylpropanamideaccording to claim 1 comprising melting or heating a solid form A ofsaid compound to 80° C. followed by cooling, wherein the solid form A ofsaid compound is characterized by: a) an X-Ray Powder diffractionpattern comprising peaks at °2θ (d value Å) angles of about 5.6 (15.9),7.5 (11.8), 8.6 (10.3), 9.9 (8.9), 12.4 (7.1), 15.0 (5.9), 16.7 (5.3),17.3 (5.1), 18.0 (4.9), 18.5 (4.8), 19.3 (4.6), 19.8 (4.5), 20.6 (4.3),21.8 (4.1), 22.3 (4.0), 23.4 (3.8), 23.9 (3.7), 24.6 (3.6), 24.9 (3.6),25.4 (3.5), 26.0 (3.4), 26.5 (3.4), 27.8 (3.2); and b) a melting pointof about 80° C.
 5. A process for the preparation of a paracrystallineform B″ of compound(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2-methylpropanamideaccording to claim 1 comprising melting or heating a solid form D ofsaid compound to 130° C. followed by cooling, wherein the solid form Dof said compound D is characterized by: a) an X-Ray Powder diffractionpattern comprising unique peaks at °2θ (d value Å) angles of about 4.4(19.9), 8.5 (10.4), 8.8 (10.0), 11.3 (7.8), 12.7 (6.9), 13.8 (6.4), 14.4(6.1), 14.6 (6.0), 15.1 (5.8), 16.1 (5.5), 16.6 (5.3), 16.9 (5.2), 18.0(4.9), 18.7 (4.7), 19.0 (4.6), 19.4 (4.55), 20.8 (4.25), 22.1 (4.0),22.7 (3.9), 23.1 (3.8), 23.4 (3.8), 24.7 (3.6), 24.9 (3.56), 25.3(3.51), 27.8 (3.2), 29.3 (3.0); and b) a melting point of about 130° C.6. The paracrystalline form of claim 1, wherein said paracrystallineform B″ is a thermotropic liquid crystalline form.
 7. A compositioncomprising a mixture of crystalline and paracrystalline solid form B″ of(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2-methylpropanamidecompound of claim 1 and a suitable carrier or diluent.